of · analysis of the data. ... case history report fom. ... 1 995; hooisma, hanninen, emmen &...

Matemal Occupational Exposure to Organic Solvents During Pregnancy

and Subsequent Visual and Cognitive Development in the Child:

A Prospective Controlled Pilot Study

Christine Siambani

A thesis submitted in conformity with the requirements

for the degree of Master of Arts

Graduate Department of Psychology

University of Toronto

@ Copyright by Christine Siambani (2000)

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Absmct

This prospective study evaluated the effects of prenatal exposure to organic solvents (OS) on

visuai and cognitive hinctioning. Children (n=33) whose mothen worked with OS during

pregnancy were matched with a referent group (n=28) on age, gender, ethnicity. matemal

education, and socioeconomic status. Groups wen compared on psychological tasks and

measures of colour vision and visual acuity. Workplace exposure was assessed by interviews

at time of initial contact during pregnancy. Prenatal solvent exposure was associated with

significant group differences on expressive language ( ~ ~ 0 . 0 1 ) and graphomotor ability

(pcO.05) adjusted for covariates. Visual test findings revealed significantly more deficits in

blue-yellow ( ~ ~ 0 . 0 1 ) and red ( ~ ~ 0 . 0 5 ) colour discrimination, as well as poorer visual acuity

(peO.05) among solvent exposed children. Frequency of colour vision loss in the exposed

group was greater than the expected rate in the general population. The findings suggest that

prenatal exposure to OS is associated with subsequent functional changes to

neurodevelopment.

Acknowledgements

This research was supported in part by the National Science and Engineering

Research Council of Canada, The Hospital for Sick Children Research Institute's Trainee

Start-Up Fund, and the Physicians Services incorporated (Ontario, Canada).

This thesis could not have been written without the aid of research associates and

menton who have betn a source of inspiration for me. I thank Patrick Arseneau and Rachel

Greenbaurn for their testing assistance and enthusiasm thmughout the study. 1 equally thank

Moira Myszak for her helpful suggestions in helping me plan the study, Alice Chiu and

Janice Wong for their dedicated effon in scoring results for reliability purposes. I am

indebted to Dr. Carol Westall and Carol Panton for their continued support and for sharing

their equipment, expertise, and space for my study. The colour vision test could not have

been included in this study without Dr. Westall's supervision and knowledge of effective

diagnostic tests for children. Thanks also to Dr. F. Vaccarrino for his contributions as my

subsidiary advisor, and Derek Stephens for his valuable input regarding the siatistical

analysis of the data. I owe Dr. Gideon Koren my deepest gratitude for his continued

enthusiasrn about my research, and for his professional advice regarding the planning of the

study. I am especially grateful to Mark Till for al1 of his help and continuous support

throughout this study. Finally, without the encouragement, patience, high standards, and

endless houn of helpful discussion of Dr. Joanne Rovet, it would not have been possible to

put this thesis into its fmd form. I sincerely thank al1 those who made this possible.

iii

Table of Contents

......................................................................... 1 . Introduction ............................... ... - 1

..................................... Organic Solvent Physical and Chemical Characteristics 4

.......................................................... Maternai Exposure. intake and Excretion 4

......................................................... Prenatal Absorption of Organic Solvents 7

Adverse Pregancy Outcornes h m Matemal Exposure to Solvents ............... 8

....................................................................... Objectives of Proposed Study 14

. . S peci fic Prediction ......................................................................... 15

2 . Method

. . ........................................................................................................ 2.0 1 Participants 16

......................................................................................................... 2.02 Procedure 18

.................................................................................... 2.03 Statistical Analyses 28

3 . Results

.............................................................................. Demographics 31

................................................................ Developmental Evaluation 33

........................................................................... Visual Functions 34

....................................................................... Cognitive Abilities -37

................................................................................................ Discussion 43

................................................................................................ Re ferences 61

..................................................................................................... Tables 74

................................................................ ..................... Figures .. ... ... 90

Appendices .................................................g..*... 94 ..................................

List of Tables

Table 1. Ordering of tests for children aged 3 to 5 yean.

Table 2. Ordering of tests for children aged 5 to 7 years.

Table 3. Distribution of occupations and type of solvent exposure.

Table 4. Demographic information of the study women and their children.

Table 5 . Developrnental milestones (in monîhs) for exposed and control groups.

Table 6. Measures of growth for both exposed and control groups.

Table 7. Maternai ratings of child's intemalizing and extemalizing behavioun.

Table 8. Frequency (in percentage) of binocular scores on the Minimalist test for exposed

and control groups.

Table 9. Frequency (in percentage) of averaged monocular scores on the Minimalist test

for exposed and control groups.

Table 10. Domain scores for exposed and control groups presented as z-scores.

Table 1 1. 2-scores for the verbal ability subtests.

Table 12. Summary of multiple ngression analyses (foward model) of the effects of

prenatai exposure to organic solvents on tasks of language ability.

Table 13. 2-scores for the visuo-spatial subtests.

Table 14. 2-scores for the visuo-motor subtests.

Table 15. Sumrnary of multiple regression analyses (forward model) of the effects of

prenatal exposurc to organic solvents on graphornotor ability.

Table 16. 2-scores on tasks of attention.

Figure 1.

Figure 2.

Figure 3.

Figure 4.

List of Figures

Mean T-score values on nanow band syndromes of the CBCl for exposed (solid)

and control (hatched) groups.

Binocular and monocular colour discrimination score as assessed by the Minimalist

test for each colour confusion line. The plots show mean colour vision score (I SE)

for the exposed (n=32) and control (n=27) group. The y-axis indicates the cap

number successfully identified. A value above one represents an error in colour

discrimination and a value of one represents a perfect sccre.

Frequency (in percentage) of binocular colour discrimination scores on the

Minimalist test for exposed and control groups. A score of 1 represents correct

identification of the lest saturated colour chip. A score above I represents a colour

discrimination deficit ranging fiom mild loss (Le. score of 2 or 3) to severe (Le.

score of 4 and above).

Binocular and averaged monocular rnean visual acuity (f SE) as assessed by the

Cardiff Car& at 1 meter viewing distance. The plot shows the results for the

exposed (n=29) and control (n=24) groups. The y-axis gives the acuity in logMAR,

where MAR is the minimum annle of resolution in minutes of arc.

Appendix A.

Appendix B.

Appendix C.

Appendix D.

-4ppendix E.

Appendix F.

Appendix G.

Appendix H.

Appendix 1.

Appendix J.

Appendix K.

Appendix L.

Appendix M.

List of Appendices

Research information fonn.

Research consent fom.

Outcome of follow-up.

Motherisk intake form.

Case history report fom.

Social strata for the Hollingshead Four-Factor Index of Socioeconomic status.

Sample FACES questionnaire.

Ranges of Family Adaptability and Cohesion Evaluation Scales (FACES).

Test protocol for young children (aged 3 - 4 years).

Test protocol for older cohort of children (aged 5 - 7 years).

Normal acuity ranges for the CardiRCards by age.

Case history: Matemal occupation solvent exposure information

Matemal report of exposure information obtained at time of pregnancy

(before) and at time of study (1 999).

vii

lntroduc tion

A large number of women are exposed to organic solvents (OS) in the workplace

(Jones & Balster, 1998), many of whom will continue to work throughout pregnancy.

Adverse reproductive health outcornes caused by matemal occupational exposure to OS

duing pregnancy range from menstnial disorders (Lindbohm, 1995) to an increased nsk of

spontaneous abortions (Holmberg, 1979; Taskinen, Lindbohm & Kemminki, 1986) and birth

defects in the O ffspring (Tikkanen & Heinonen, 1 988; Lindbohm, Taskinen, Sallmen &

Hemminiki, 1990; McMartin, Chu, Kopecky, Einarson & Koren, 1998; Khattak, et al., 1999).

These cm occur as a result of exposure to a single substance or a combination of toxic

substances in the workplace.

While abnormal central nervous system (CNS) hctioning of the fetus is also a likely

consequence of prenatal solvent exposure, very few studies have examined long-term effects

of matemal solvent exposure (Eskenazi, Gaylord, Bracken & Brown. 1988; Kersemaekers,

Roeleveld &Zeilhuis, 1995). Of the studies conducted, most have placed greater emphasis on

basic teratology (i.e. offspring viability, morphology, growth) than offspring behaviour. As a

result, we are faced with an incomplete database for safety assessrnent because many OS, for

which there is basic teratology data, lack measures of sensory and behaviod functioning.

This lack of information is of concem because lower doses of OS, such as those cornmonly

found in the workplace, may induce more subtle manifestations of toxicity in the absence of

physical malformations. Furthemore, functional deficits can occur after the time for

malformations while the brain is still developing.

A starhg point for understanding the long-teim effects of prenatal exposuie to OS can

be sought h m past studies in adults exposed occupationaily to OS. In contrast to the paucity

of information on the neurotoxic effects of prenatal exposure, the effects of occupational

exposure to OS in adults have been well studied. One particularly useful marker of early CNS

dyshinction following neurotoxic exposure in adults is visual h t ioning. Previous studies

have demonstrated that continued exposure to a wide range of OS at levels encountered at the

workplace can produce visual deficits including acquired dyschromatopsia (Raitta et al., 198 1;

Horan et al., 1985; Mergier, Blain & Lagacé, 1987; Mergier et al., 1996; Gobba et al., 1% 1;

Gobba, Cavalieri, Bontadi, Tom & Dainese, 1995; Fallas, Fallas, Maslard & Dally, 1992;

Campagna et al., 1995, Carnpagna et al., 1996, Muttray, Wolters, Jung & Konietzko, 1999),

modi fied electroretinal responses (Blain, Lachapelle & Molotchniko ff, 1994). reduced

contrast sensitivity threshold (Mergler, 1995), decreased visual acuity, optic neuritis, and

vision b l h n g (reviewed in Boyes, 1992). Chromatic discrimination is particularly sensitive

to the subtle effects of neurotoxic exposure because changes to colour vision are not

necessarily accompanied by functional disorders. Because changes in colour vision may be

more easily detectable before overt symptoms manifest, testing chromatic discrimination

capacity may constitute an important early indicator of neurotoxic darnage in children exposed

in utero to OS.

The effects of exposure to OS on cognitive functioning is another area well researched

in adults. Numerous studies have associated occupational solvent exposure with adverse

effects on psychological and neurological functioning. The studies covered groups such as

housepainters (Lundberg et al., 1 995; Hooisma, Hanninen, Emmen & Kulig, 1 994), tiberg lass

builders (Cherry et al., 1980; Mutti et al., 1984; Tsai and Chen, 1996; Jegaden, Amam,

Simon, Legoux & Galopin, 1993), industrial painters (Elofsson et ai., 1980; Linz et al., 1986;

Kishi, Harabuchi, Katakura, Ikeda & Miyake, 1993; Ruijten et al., 1994) and workers in

Prcnatal Exposurc ta Organic Solvents 3

reinforced plastics industry (Lindstrom, HkkOnen & Hemberg, 1976; HbkOnen, Lindstrorn,

Seppalainen, Asp & Hemberg, 1978; Cherry, Rodgers, Venables, Waldron & Wells, 198 1 ;

Matikainen, Forsman-Gionholm, P f m i & Juntunen, 1993; Mergler et al.. 1996), paint

(Fidler, Baker & Letz, 1987; Lee & Lee, 1993; Colvin, Myers, Nell, Rees & Cronje. 1993) or

adhesive factones (Escalona, Yanes, Feo & Maizlish, 1995). Workers exposed ?O OS have

show impairments in one or more of the following f'unctional areas: attention, executive

function, short-tem memory, verbal fluency, motor abilities, visuo-motor and visuo-spatial

skills, as well as poorer performance on tasks of leaming. Given the well documented effects

on neuropsychological and neurological functioning in adults exposed to OS, studies should

focus on the potential fùnctional deficits in children exposed to OS in utero.

Based on past studies, we see that OS have an &ni@ For the nervous systern and are

linked to visual and cognitive deficits in adults. Given that the fetus is highly susceptible to

neurotoxic insult, it is likely that prenatal solvent exposure will affect its neurodevelopment.

Thus, the following question was posed: What are the effects of matemal occupational

exposure to OS during pregnancy on visuai and cognitive development in the offspring? This

question was investigated by (a) reviewing the evidence linking abnomal development of the

fetus to matemal solvent exposure, (b) designing a snidy to investigate the effects of prenatal

exposure to OS on visual and cognitive development, and (c) testing the experimental

hypotheses using a prospective controlled design. Based on the results of the current snidy,

preliminary evidence of adverse developmentd outcornes associated with materna1

occupationai exposure to OS is presented. As well, methodological issues related to this area

of research are addressed.

The tenn "organic solvent" refers to a generic classification for a chemical compound

or mixture used to extract, dissolve or suspend non-water soluble materials (Arlien-Sobgrg,

1992). Most OS are liquids that boil in the range of 7S°C to 220°C and have structurally

diverse, low rnolecular weight physiochemical properties. Solvents are physicaily

charactenzed as volatile, lipophilic, and highly soluble. They are grouped according to their

chemical structures. These include: hydrocarbons, which are divided into the aliphatic

hydrocarbons (e.g. hexanes, pentanes, octanes) and the ammatic hydrocarbons (e.g. berizene,

styrene, toluene, xylene); halogenated compounds (e.g. carbon tetrachloride. methylene

chlonde, trichloroethy lene, perchloroethylene); alcohols (e.g. methanol. ethanol); gl yco 1s (e.g.

ethylene, propylene glycol); ketones (e.g. methyl ethyl ketone) and complex solvents (e.g.

petroleurn ethen, cubber solvent, varnish, painters' naphtha, minera1 spirits). Understanding

these basic structures may allow us to extrapolate data on one solvent to another one that is

c hemically similar.

Matemal exposure to OS is widespread. It can occur in the workplace, through

household product use, environmental pollution and tobacco smoking. Occupations with

potential chemical exposures include laboratory technicians, graphic designers, painters, hair

dressers, photo developers, dry cleaners, and workers in clothing and textile industries.

Solvents are also used by manufacturers of paints, glues, coatings, dyes, and polymers, as well

as in the preparation of pmcessed foods and phannaceuticals. In household producis, OS are

Prenatal Exposurc to Organic Solvents 5

found in spray adhesives, spray paints, oil paints, varnishes, nail removers and felt-tip pens.

In environmental pollution, OS have been reported as a contaminant in drinking water

(Witkowski & Johnson, 1992). and as air pollution (Marshall, Gensburg, Deres & Cayo,

1997). Toluene is also inhaled through tobacco smoking. It has been reported that smokers

inhale 80 to 160 pg toluene per cigarette and have approximately a onefold increased

concentration of toluene in blood (median 2.0 pgL) cornpared to nonsmokers (median 1 . i

pg/L) (cited in von Euler, 1994). Another common route of solvent exposure that is on the

rise today is deliberate exposure in pursuit of an intoxicating solvent "high" (Henh, Podnich.

Rogers & Weisskopf, 1984; Jones & Balster, 1998). According to a national survey of high

school students in the United States, approximately 17% of adolescents have sniffed inhalants

at leasi once in their lives (Johnston, Malley & Bacban, 1994 cited in Jones & Balster,

1998).

Certain properties of OS affect exposure intake. Solvents that are both lipid and water

soluble can pass through intact skin most easily because skin has both water and lipid

compartments. Because of their volatility, OS cm also easily enter the bloodstream through

the alveoli of the Iungs. Measures of solvent inhalation show that between 40 to 80% of the

inhaled dose is absorbed at rest. The total amount absorbed increases with exercise and

pregnancy as blood flow to the lung and alveolar ventilation increases (Welch, 1993). Once

the OS are absorbed, they are immediately distributed throughout the body with high affinity

for lipid-nch tissues such as myelin or white rnatter in the brain.

Metabolism and excretion kinetics are highiy variable arnong compounds. Matemal

excretion of unchanged OS occurs primarily through the Lungs as expired air or they may be

metabolized in the liver and eliminated in the urine. The biological half-life of OS is typically

in the range of several hours (Baker, Smith & Landrigan, 1985) making the timing of sample

collection relative to the termination of exposure critical for reliable estimates of uptake. A

solvent with a half-life longer than 12 hours will accumulate over the work week, resulting in

a higher body hurden at the end of the week fiom the same exposure conditions. A detailed

description of the excretion kinetics and biotransformation reactions that influence the fate of

absorbed OS is beyond the scope of this review.

nie amount of OS retained is dificult to quanti@ because it is dependent on several

solvent- and human-related factors. Solvent-related factors incfude: the level and duration of

exposure, specific physiochemical features of each solvent, the use of protective equipment,

and synergistic effects of sirnultaneous exposure to solvent mixtures (reduced rate of

metabolism of one solvent in the presence of other OS) (Baker et al., 1985). With respect to

human-related factors, physiological Factors such as body build, percentage body fat, blood

and tissue solubility affect the pharmacokinetic profile of OS (Sato, Endoh, Kaneko &

Johanson, 199 1). Toxicity of OS also varies according to levels of physicai exercise

(associated with increased pulmonary capillary blood flow), diumal metabolic cycles, and

alcohol use (Cherry, 1993). Baker et al. (1985) reported that ethanol ingestion decreases the

metabolic clearance rate of xylene by about one half-life. This is due to a metabolic

interaction betwecn xylene and alcohol which are degraded by the sams cnzyme (aldehyde

dehydrogenase). As a result of the ethanol-induced metabolic inhibition, concurrent exposure

to alcohol and OS slows clearance of the solvent and might be expected to prolong internai

exposure to the neurotoxin. Thus, biological monitoring alone cannot detennine that an

Prenatal Exposure to Organic Solvents 7

exposure is safe or without reproductive risk. Exposure estimates obtained by biological

monitoring must be combined with adequate health data to determine risk.

It is important to note that many factors can affect the rate of transfer of drugs and

chemicals fiom matemal blood to the fetus. These include: the degree of lipid solubility and

protein binding, the pKa of the compound, placentai blood flow, placental function, and the

degree to which active transport occurs (cited in Welch, 1993). As a general nile. compounds

that have a high aflinity for lipid, a low degree of ionization, and a molecular weight less han

1000 are rapidly transfened across the placenta. Since OS fit this description by definition,

many OS can cross the placenta1 barrier into the arnniotic fluid where they are ingested and

dermally absorbed by the conceptus.

Studies in both animals (Stoltenburg-Didinger, Altenkirch & Wagner, 1990) and

humans (Laham, 1970) have exarnined transplacental dimision of OS. In one study of

pregnant mice, placenta1 transfer of radiolabeled toluene, xylene, and benzene was studied

using autoradio-graphic and liquid scintillation rnethods (Ghantous & Daneilsson, 1986 as

cited in Valciukas, 1994) and the distribution of the OS and their metabolites was obsewed at

difFerent time intervals after a ten minute period of solvent inhalation. Results showed that

irnmediately after inhalation, the OS reached high concentrations in the mothers' lipid-rich

tissues (i.e. brain and fat) and in perfùsed organs such as the liver and kidney. M e r one hou,

these were eliminated h m al1 matemal tissue except fat. Metabolites reached peak levels

between 30 minutes and one hou fier inhalation and were eliminated rapidly thereafter. It is

important to note that at dl stages of gestation, placental m s f e r of aonmetabolized OS was

Prcnatal Exposurc to Organic Solvents 8

observed in the fetus and in amniotic fluid immediately, and up to one hou after matemal

inhalation.

The fetus is considered especiaily vulnerable to CNS insult for severai reasons. First,

the incomplete development of the blood-brain barrier makes the fetus more susceptible to

neurotoxic insult. Second, the fetus is at increased risk due to the relatively high lipid content

of the developing brain compared to the rest of the body. niird, based on phwnacokinetic

concepts, the mechanisms for detoxification are not fùnctioning due to immaturity of the

necessary organs for solvent metabolism. Thus, due to a number of characteristics inherent in

the biological system, the fetus is more vulnerable to toxic substances.

Animai studies have reported lhat a variety of OS cross the placenta resulting in

increased embryotoxicity (reflected by lower conception rates and smaller litter size),

miscamiage, and structural abnormalities (Stoltenburg-Didinger et al., 1990). Malformations

following prenatal solvent exposure in animals include hydrocephaly, exencephaly, skeletal

defects, and cardiovascular abnormalities (Stolenburg-Didinger et al., 1990; Schwetz et al.,

1992; Narotsky & Kavlock, 1995; Kishi, Chen, Karakura, ikeda & Miyake, 1995; Thel&

Chahood, 1997). A delay in the maturation of the cerebellar cortex (Stolenburg-Didinger et

al., 1990) and changes to the lipid class composition of the cerebral cortex have also been

reported (Kyrklund, Alling, Haglid & Kjellstand, 1983). Studies of behavioural toxicity in the

O ffspring of animals following matemal exposure to OS have revealed significant dose-

dependent efflects such as delayed mflex and motor development (Kishi et al., 1995), altered

rates of behaviourel habituation to novel environments (Bomschein, Hasting & Manson,


1980), deficits in spatial learning and memory (von Euler, Ogren, Li, Fwte & Gustafsson,

1993), and increases in spontaneous activity (Kishi et al., 1995). Interestingly, these effects

were observed in the absence of overt matemal toxicity.

Matemal exposure to OS in the workplace has been associated with various disorden

of reproductive health including reduced fertility and menstnial disorders (Lindbohm, 1995).

Reduced fertility in animals and humans is rnost clearly associated with exposure to glycol

ethen and their acetates. Menstrual disorders, on the other hand, are most commonly

associated with exposure to benzene, toluene, xylene, styrene, carbon disulfide, and

fomaldehyde. Matemal occupational exposure to OS during pregnancy has also been

associated with increased rates of spontaneous abortion (Hemminki, Franssila & Vanio, 1980;

Taskinen, Lindbohm & Hemminki, 1986), but not al1 studies have confirmed this association

(Axelsson, Lutz & Rylander, 1984). Other studies have focused specifically on congenital

malformations (Le. cle A palate, cardiovascular malformations) following prenatal solvent

exposure Ofolmberg & Nminen, 1980; Blomqvist, Encson, Kallen & Westerholm. 198 1 ;

Hemrninki, Mutanen, Salonieni & Luoma, 198 1 ; Holmerg & Kurppa, 1982; Kurppa et al.,

1983; McDonald, Lavoie, Cote & McDonald, 1987; McDonald et al., 1 988; Tikkanen &

Heinonen, 1988; Lindbohm et al., 1990; Kersemaekers et al., 1995; Khattak et al., 1999). In a

recent meta-analysis (McMartin et al., 1998), an increased risk of major malformations and a

trend towards spontaneous abortions were detected in pregnancy outcome following matemal

exposure to OS. In another study (Lindbohm, 1995) children whose mother's were exposed

to OS during pregnancy were reported to have higher incidences of leukemia and brain Nmon

than nonexposed chilchen. It is important to note that these adverse effects have been


observecl even in mothers exposed to OS near or below the standard occupational exposure

levels (von Euler, 1994).

In general, studies in humans and animals pmvide evidence of an association between

solvent exposure during pregnancy and congenital defects in the offspring. in the human

studies, however, it is nearly impossible to identify a specific solvent responsible for the

increased risk of an adverse outcome because most of these studies involved populations

occupationally exposed to a mix of OS. Because the level of exposure in human teratology

studies is usually unknown, it is difficult to determine which occupations are at increased risk.

Based on the current data, women should be advised to minimize exposure to OS dunng

pregnancy. This exposure reduction must occur early in pregnancy to prevent effects during

critical penods of organogenesis, and should extend throughout pregnancy to protect the

developing organism.

The fact that numerous OS are ubiquitous in the environment has also raised

considerable attention over the potentiai for teratogenesis. In a study by Marshall et al.

(1 997), an elevated risk for CNS and musculoskeletal defects was found among offspring of

women exposed to OS fiom hazardous waste sites during pregnancy. This association shows

that fietal neurodevelopment may be disrupted even by indirect exposure to OS in the form of

pollution. In another study, Witkowski and Johnson (1992) investigated the association

between organic solvent water pollution and low birth weight in Caucasian residents in

Michigan. Results showed a positive relationship between water pollution caused by benzene

and chlorinated solvents and per cent of low-weight births. Although these correlations do not

si@@ causation, there is reason for concem that environmental pollution rnay be linked to

Prcnatal Exposure to Organic Solvents 11

epidemics of birth defects. However, this relationship should be explored in greater detail in a

prospective rather than retrospective study design, in order to have a more accurate record of

pollution during pregnancy.

inhalation ofpaint or glue is a popular fonn of recreational dmg abuse, particularly

arnong teenagers and young adults. Toxic effects resuiting from chronic solvent abuse

include: cerebellar degeneration, cortical atrophy, impaired mental and intellectual

performance, and in some cases, sudden death fiom suspected cardiac arrythmias (Hersh,

Podmch, Rogers & Weisskopt 1984). Patients suffenng h m chronic abuse of toluene also

show optic neuropathies and changes in electroretinograms (Toyonaga, Adachi-Usami &

Yarnazaki, 1989 as citrd in Muttray et al., 1999). Matemal complications of toluene abuse

during pregnancy include renal tubular acidosis, hypokalemia, hypocalcernia, cardiac

antiythmias, rhabdomyolysis, and premature labour (Arnold, Kirby, Langendoerfer &

Wilkins-Huang, 1994). Teratogenic effects in children bom to mothen addicted to OS dunng

pregnancy have shown similarities to those with fetal alcohol syndrome (Pearson, Hoyme,

Seaver & Risma, 1994)'. Abnomal features include microcephaly, a Bat nasal bridge, a

hypoplastic mandible, short paipebral fissures, mildiy low-set ears, a sloping forehead, and

uncoordinated arm movements (Hersh et al., 1984). Analysis of the pattern and nature of

associated mal formations suggests a deficiency of cranio facial neuroepitheli um and

mesoderrnal components due to increased embryonic ce11 death (Pearson et al., 1994).

Neurobehavioural effeçts observed in children exposed to solvent-sni ffing mothen include

' This is no< surpcising given that alcohol is a type of rolvcnt.


delayed development with greater language deficits, hyperactivity, and attentional problems

(Hersh et al., 1984). It should be noted, however, that studies of children with toluene

embryopathy are ofien confounded by exposures to other potential teratogens including

alcohol, cocaine or heroin.

One prospective study by Eskenazi, Gay lord, Bracken and Brown (1 988) compared

the neurobehavioural development of forty-one 3.5 year-old children exposed to OS in utero

with that of age- and gender-matched children whose mother's were not exposed to OS.

Children's development was evaluated directly using the McCarthy ScaIes of Children's

Abilities and by parental report includhg the Childhood Personaiity Scale and Conners Parent

Hyperactivity Rating Scale. Results showed no significant differences in cognitive stanis o n

any of the McCarthy scales, nor in parental ratings of the child's personality. Eskenazi et al.

suggested a number of factors that could explain this lack of significant differences. First, the

study had inadequate power because of insufficient sample size. Second, insensitivity of the

outcome measures may have rnissed some differences between the solvent-exposed and

control group or it is also possible that the offects do not emerge until a later age when more

complicated cognitive skills such as reading develop. W d , the exposure levels in this study

may have been too low to produce noticeable neurobehavioural deficits. However, analysis of

the mothers' reports of their child's developmental milestones revealed a significant temporal-

response relationship. Results showed that increasing length of exposure was related to older

ages at which the children began to walk, but this effect was not found for the other

developmentai milestones.


In another study by Kenemaekers et al. (1997)' the neurodevelopment in offspring

exposed to OS in utero was investigated using a large historical cohort of hairdressen in The

Netherlands. Nine thousand hairdressen were age-matched with 9000 clothing sales clerks

who served as the reference gmup. Women completed a questionnaire on their reproductive

history, including questions on the ages of their child's developmental milestones, and the

occurrence of seizwes during Bver. Results showed significmt delays in speaking Tint words

and first sentences among children of hairdressers boni between 1986 and 1988, but not

among those bom between 1 99 1 and 1 993. Seizures during fever had occurred more O ften

among children of hairdressers for both study periods. The results of this explorative study

indicate more adverse neurodevelopmental effects among offspnng of hairdressers in the

earlier (1 986 to 1988) compared to the later period (1991 to 1993). This difference was

suggested to reflect changes in chemicals used by hairdressen over tirne.

To date, very little is known about the effects of matemal occupational exposure to OS

on neurobehavioural functioning in the offspring. Most of the research in this area has

focused on pregnancy outcome or the incidence of major malformations. Although it is very

important to know the risk of major malformations, this approach is of questionable value in

identifying the effects of minor, and usually long-tenn exposure to OS. Nevertheless, thete is

reason for concem that prenatal exposure to OS may be associated with subtle changes to the

developing CNS. There is a need for considerable work, employing continuous measures of

behaviour, to evaluate effects of prenatal exposure to OS on the developing CNS at dosages

below those that pmduce death or visible anomaly.

ves of SQ&

The primary objective of the present study was to investigate whether matemal

occupational exposure to OS during pregnancy is associated with changes to cognitive and

visual development in the o f f s p ~ g . The specific focus on the occumnce of colour vision

deficits was prompted by the observation that low-level exposure to OS cm cause changes to

the ntina and optic nerve in workers exposed to OS. Since the development of the visual

system begins in the first trimester, it was predicted that matemal exposure to OS during

pregnancy will disnipt normal visual development in the offspring. These changes were

predicted to result in long-term perturbations on overall colour vision and visual acuity.

Prenatal exposure to OS was also expected to impair cognitive functioning as a result of subtle

alterations in early bnin development. In this study, a broad neuropsychological repertoire

was used to assess cognitive outcome in young children exposed to OS in utero. The test

battery included tasks shown in the research literature on adults to be sensitive to solvent

exposure. The specific cognitive abilities evaluated in this study included language. attention.

visuo-spatial and visuo-motor skills.

The research approach of the current study involved a prospective controlled design.

This type of design is preferred because it avoids many of the problems associated with

retrospective designs. For example, data collected retrospectiveiy may be confounded with

memory bias reflecting outcome ofpngancy (Bar-Oz, Moretti, Mareels, Van Tittelboom &

Koren, 1999). In other words, the mother of a child with a behavioural problem may actively

try ta recall events that lead to the deficit, whereas the mother of a healthy child is more likely

to forget any potentially hannfùl exposuns during the pregnancy. Thus, use of prospective

Prenaîal Expom to Organic Solvents 15

data offers a more reliable source of exposure information that cm be used to address

questions about childfen' s fùnctioning following prenatal exposure to OS.

This study addnssed the following specific questions: (1) Does prenatal exposure to

OS affect colour vision and visual acuity? (2) What is the impact of prenatal solvent exposure

on language, attention, visuo-spatial and visuo-motor ability? and (3) What is the relationship

between the dose of exposure and the incidence of adverse developmental effects? In addition

to measures of visual and cognitive functioning, this study assessed growth of child,

developmental milestones, and child problem behaviours using self-administered

questionnaires completed by the mother. Finally, methodological issues related to this area of

research are discussed.

It was hypothesized that children exposed to OS in utero would show deticits in colour

vision and visual acuity compared to a sample of matched controls. Given the predicted effect

of damage to the visual system in solvent-exposed children, more deficits were expected to

occur on tasks of visuo-motor and visuo-spatial ability than on tasks of language and

attention. A dose-response relationship was predicted with poorer performance in children

whose mothers were exposed to higher levels of OS. Finally, a temporal-response

relationship was expected with more deficits associated with increasing length of exposure to

OS*

Prenatal Exposure to Organic Sotvents 16

Method

Al1 participants were recruited from the Motherisk Program, a consultation service for

teratogenic exposure during pregnancy at The Hospital for Sick Children in Toronto, Ontario.

The study cohort consisted of 6 1 children aged 3 to 7 years whose mother's had been

counseled between 1992 and 1996 by the Motherisk Program, Ali women were contacted

through an initial phone cal1 by the experimenter who explained the purpose of the study.

Women interested in the study were sent a description of the research (see Appendix A)

followed by another phone cal1 to discuss any questions. Children whose parents agreed to

participate came to The Hospital for Sick Children for a full rnoming or full aftemoon session.

Al1 children were tested between March 1999 and October 1999. The protocol for the study

was approved by the Research Ethics Board at The Hospital for Sick Children. Informed

consent fiom the parents was obtained at the time of testing in accordance with the Research

Ethics Board (see Appendix B).

Between 1992 and 1996, 1 17 women who lived within a 4-hou dnving radius of

Toronto contacted the Mothensk Pmgram with regard to occupational exposure to OS. Of the

L 17 women, 65 were successfùlly contacted and screened by telephone while 52 were lost to

follow-up. Fifteen of the women contacted were excluded for the following reasons:

pregnancy resulted in miscarriage (n=4), premature bhth (n=l), removed themselves nom the

exposure (n=3), autistic child (n=l), endocrine disorders (n=2), depmsion during pregnancy

(a=l), exposed to teratogens other than OS (n=2), and did not speak English (n=l). The

remaining 50 women were mailed a package that Ulciuded a letter describing the purpose of

the study, methodological information and several questiomaires. Shortly thereafter, women

were contacted again by phone and asked if they were interested in participating with their

child in the study. Thirty-five women agreed to participate. Of the 35,2 women missed their

appointments and then lost interest, leaving 33 women in the final group. Since 4 women

were occupationally exposed to organic solvents for more than one pregnancy, the sample of

children in the exposed group consisted of 37 subjects. Of the 37 children tesied, the data

from 4 were subsequently excluded for the following reasons, some of whch were not

disclosed at the initial phone interview: mother used recreational dnigs during pregnancy

(n-1 ), premature birth (n=2), mother had surgery at 2 months of pregnancy (n=L ). The final

sample of children in the exposed group consisted of 33 subjects with a rnean age of 4.6 * 1.17. Colour vision data was omitted fiom the analysis for one child due to congenital colour

vision defects.

Mothea and their children in the solvent-exposed group were matched with a referent

group of 27 mother-child pain on age (a months), gender, ethnicity, parental marital and

socioeconomic status. Referent mother-child pain were recruited fiom a database of wornen

who had contacted Mothensk for exposure to a non-teratogenic agent during pregnancy. A

non-teratogen is defined as a medicinal or environmental substance that has not been

associated with a specific risk of major malformations, miscimiage or abnormal neurological

development. The database consisted of 80 women who were interviewed by phone to ensure

they met the criteria for inclusion as a referent subject. Of the 80 woman contacted, 70 met

the cnteria for inclusion as a referent subject. During this initial contact, women were asked

questions about their child and farnily socioeconornic status for the purpose of matching.

Women were mbsequentiy contacted and sent Unformation about the study if a match was

found with a mother-child pair in the exposed group. Of the 33 children who were originally

Prcnatal Exposurc to Organic Solvcnts 18

tested as matched controls, 5 were omitted for the following reasons: premature birth (n=l),

underdeveloped optic nerve (n=2), behavioural problems (n=l), birth complications (n=l ), for

a final sample of 28 controls with a mean age of 4.9 * 1 .O9 (see Appendix C for a summary

outcome of follow-up).

Solvant-txposed participants were seiected based on the following inciusion cnteria:

only women who were exposed to OS for at least 5 hours per week, and exposure to OS

spanned at l e s t 2 months of pregnancy. Al1 participants abstained fiom alcohol consumption

and recreational dmg use dunng the entire pregnancy, and al1 children were neurologically

normal.

Participants in both groups who met the following cntena were excluded from the

snidy: women exposed to known teratogens other than OS (e.g. lead in paints, carbon

monoxide), women with a psychiatrie illness or endocrine disorder during pregnancy, children

of non-English speaking families, children bom prematurely at less than 36 weeks gestational

age, and children who were believed to be at greater risk of showing abnorrnal visual

development due to family history of heritable retinal disease or congenital colour vision loss.

Procedure

At the time of original contact with the Motherisk Program, a trained counselor

interviewed each woman about her work conditions, use of protective barriers, the distance

from exposure, the number of hours she was exposed to the chemicai per day, and whether she

experienced adverse effects upon exposm. This information was collecteà separately for

diflerent types of OS using a standard questionnaire (see Appendix D). Organic solvents to

Prenatal Exposurc to Organic Solvents t 9

which women were exposed occupationally included aromatic and aliphatic hydrocarbons,

halogenated compounds, alcohols, ketones, glycols and related compounds. Information

about intrauterine exposure to alcohol, tobacco, and other medicinal and recreational dnigs

during pregnancy was also obtained at this time.

Demographic idormation (marital status, education, ethnicity, age, occupation. etc.).

medical history of the mother and child, deveiopmental milestones of the chiid, and duraiion

of breast feeding were obtained using the Case History Report (see Appendix E), which was

compieted by al1 women who participated in the study. Standardized information about

socioeconomic status (SES) fiom ail women enrolled in the study was collected using the

Hollingshead Four Factor Index of Social Status (Hollingshead, 1975). This measure

provides r xighteil average of the mother's and father's occupational and educational level.

Numencal ranges for the social strata of the Hollingshead Four Factor Index are listed in

Appendix F.

In order to control for between-group differences in family functioning, parents were

asked to complete the Family Adaptability and Cohesion Evaluation Scales (FACES III)

(Olson, 1985). FACES UI is a 20-item questionnaire that enables the examiner to classify the

family in terms of (1) family cohesion, ranging fiom disengaged to enmeshed, and (2) family

adaptability, ranging fkom ngid to chaotic (see Appendix G for a sample FACES

questionnaire). This measure is designed to obtain both perceived and ideal family

functioning and to identify the type of family dysfunction. Appendix H lists the range of

scores for categoriang family cohesion and adaptability.

No current information exists on the smetion of organic solvenîs and / or thcir metablites through brcast feeding.

Parents were also asked to complete the Child Behaviour Checklist (CBCL)

(Achenbach, 1991), which is a widely used instrument for providing a standardized, reliable.

and valid description of the child's problem behaviours and social competencies5. Depending

on the age of the child, parents completed either the CBCLU-3 (for children that are less thm

4 years) or the CBCL\4-18 (for children older than 4 years). This questionnaire consists of

100 (for the CBCLV -3) or 1 13 (for the CBCLSJ-18) age-appropriate descriptions that are

rated by the parent on a 3-point scale fkom "not true" to "often hue". The problem behaviour

scale provides indices of total behaviour problems, as well as intemalizing (Le. over-

controlled neurotic-like behaviom) and extemalizing behaviour problems (Le. under-

controlled conduct problem behaviours). The scale also assesses a variety of narrow-band

problerns including aggressive and delinquent acts, withdrawal, somatic cornplaints,

anxiousness or depression, and attention, social, and thought problems. The CBCL is widely

used in developmental research and has excellent psychometric properties (hi& inter-parent

reliability for social problems (I-.77), attention problems (r=.79), deiinquent behaviour

( ~ 7 8 ) . aggressive behaviour (r=.79), extemalizing (r;.80), and overall test-retest reliability

of 0.89).

The administration of the tests to the children was approximately two 1 hour blocks

with a 5 to 10 minute break separating the blocks. Testing was conducted in a quiet room in

the Child Assessment Laboratory of the Psychology Department at The Hospital for Sick

Children. Al1 children were assessed by a ûained examiner working under the supervision of

' Only the CBCLM- 18 has cornpetnice scaies

a registered psychologist. A parent was pennined to observe the experimental setting upon

request of the child. Observers were asked to sit outside the view of the child and to refrain

from communicating with the child. Since the expenmenter was not blind in this snidy, al1

subjective outcome scores (Design Copying and Visuo-rnotor Precision) were scored by

another person who was blind to the child's condition to control for potential expenmental

bias in scoring.

At the conclusion of the study, children received a gi ft (a "Tails" book and

audiocassette produced by the theatre group at The Hospital for Sick Children), and a

certificate of appreciation. The adults were reimbursed for travel expenses (gas, mileage and

parking, or public transit) incurred in coming to The Hospital for Sick Children. A detailed

neuropsychological report and vision test results were provided to the parents wiihin two

months of the assessment. Children who were suspected of having a visual defect were

referred to the ophthalmology c h i c at The Hospital for Sick Children.

*. . ur Vision

Colour vision was assessed by using the Mollon-Rem Minirnalist Test (M-R-M)

(Mollon, Astell & Reffin, 1991; Mollon & Re&, 1994). To evaluate the extent of colow

vision loss, the qualitative details and extent of chromatic deficit were scored on a chart on

which differential chromatic loss in the red @rotan), green (deutan), and blue-yellow (tritan)

range were identified. The Minimalist Test was selected because it has been shown to classify

childm as young as three years with dichromatic colour defects, and unlike many other

colour vision tests, it is sensitive to blue-yellow dyschromatopsia (Leat, Shute, & Westall,

1999). Another important advantage of this test is it can be used successhilly with children

whose visuai acuity is low.

Prenatal to Organic Solvents 22

The M-R-M test consists of thm series of coloured caps coinciding with the protan

(red), deutan (green) and tritan (blue-yellow) confusion axes with a range of six saturations

along each axis. Each chip is assigned a number from 1 to 6 with 1 representing the lest

saturated and 6 the most. The examiner randomly places 5 achromatic chips (varying in

saturation) and 1 chromatic chip on a black table illuminated by standard source C

illumination (Gretaghkcbeth, 617 Little Britain Rd., New Windsor, W. 12523). The test

begins with a saturated orange chip which does not lie on the confusion line. The child was

told that "One of the chips is different. Can you find the chip that is different?". To ensure

compnhension of the task instructions, the examiner did not proceed with testing until the

child succeeded on this pretest. The test continues with the third chip in the protan. deutan or

tritan series. presented one at a time, with random ordering of the three colour series. If the

child accuately identifies the coloured chip, a Iess saturated chip is chosen. This process is

repeated until the child either identifies al1 the chips, for which a score of I is achieved, or

incorrectly identifies the chip for two out of three trials, for which the score is recorded as the

last chip identified correctly. If the child fails to recognize the coloured chip, then the next

chip with higher saturation is introduced. This process is continued until the highest saturated

chip for which the score is recorded as 6. A quantitative evaluation of colour vision outcornes

was carried out by determinhg the score of the least saturated coloured chip identified

correctly. Since acquired dyschromatopsia can be unilateral, the test was performed

monocularly and binocularly. Although there was no time lirnit placed on the subjects, the

test usually took about 6 minutes to complete.

The Cardiff Cards (Adoh, Woodhouse & Oduwaiye, 1992) were used to assess

binocular and monocular acuity. This test uses familiar pictures (e-g. fish, car, dog, duck) of

constant overall size, positioned either at the top or bottom of each card (2 1 x 29.5 cm). The

outline of each figure consists of a white band, flanked on either side by a black band, the

black band being one-haifthe width of the white band. The average luminance of the black

and white bands equals that of the gray background. The angular subtense of the black band

defines the visual resolution in minutes of arc. The card with highest resolution that can be

detected defines visual acuity. Acuity was assessed based on the principle that when the

target figure is presented beyond the observer's resolution limit, it disappears into the gray

background, and nothing is seen. Visual acuity was tested at 1 meter viewing distance and

was scored as the log of the minimum angle of resolution (1ogMA.R) in minutes of arc where O

logMAR is equivalent to 20120 vision and a value mater than O logMAR reflects less than

20120 vision (see Appendix K for a sample of the Cardiff Card scoring sheet).

Clinical tasks were selected fiom validated and standardized test batteries to provide

measures in four domains: verbal ability, attention and executive huictions, visuo-motor

skills, and visuo-spatial ability (Appendix 1 lists the tests in each functional domain for

children aged 3 to 5 years and Appendix J lists the tests in each functional domain for children

aged 5 to 7 years). Criteria for inclusion of a test in the battery include its (1) sensitivity to

measure a particular cognitive huiction, (2) nliability, (3) construct validity, and (4)

practicality and time constraints for use with young chilchen. Furthemore, al1 tests had a

reasonable range of performance outcome measures. The test battery was believed to sample


a variety of different types of cognitive abilities using multiple measures to truly assemble a

picture of impaired versus retained abilities in the face of exposure.

Since visual dysfunction has been reported predominantly in adults exposed to OS. the

primary focus of the neuropsychological testing was visuo-spatial and visuo-motor abilities in

children exposed to OS in utero. Tests of verbal ability were also included in this study in

order to assess whether both groups of children understood task instructions and couid express

themselves equally well. Likewise, tests of attention were included to assess the child's

attentional capacity since deficits in sustaining attention could possibly account for the child's

performance on other neuropsychological measures. While maintaining focus on visual

functions. the wide selection of tasks used in this study has the ability to tap distinct

perceptual and cognitive functions that may possibly be additionally impaired. The order of

tests within blocks (see Table 1 and Table 2) was counterbalanced across participants.

Insert Tables I and 2 about here

Expressive language ability was assessed using selectike language subtests fiom the

Developmental Neuropsychological Assessrnent (NEPSY) (Korkman, 1 W8), as well as the

Expressive One-Word pic^ Vocabulary Test (Revised) (EOWPVT-R, Gardner, 1979). The

NEPSY language subtests included: Body Part Naming, which is an expressive language test

requiring the child to name body parts on a pichm of a child; Speeded Naming, which

quires rapid naming of recuning sizes, colours, and shapes; and Verbal Fluency, which

mesures the child's ability to generate words within a category. The EOWPVT-R requires

naming many pictures of objects and groups of objects.

Receptive language ability was estimated using the NEPSY Phonological Processing

subtest which consists ofsound blending and word completion, the NEPSY Cornprehension

of Instructions subtest, which assesses the child's ability to process and respond to verbal

instructions of increasing syntactic complexity, as well as the Peabody Picture Vocabulary

Test - Third Edition (PPVT-III, Dunn & Dunn, 198 1) which requires the child to point to one

of four pictures named by the examiner. In addition to measunng receptive language ability,

the PPVT-III also served as an estimate of the child's I.Q. since this test is highly predictive of

intelligence.

The Wide Range Assessment of Visual Motor Abilities (WRAVMA) (Adams &

Sheslow, 1995) Pegboard subtest, and the NEPSY Visuo-motor Precision, Design Copying,

and Imitating Hand Positions subtests were used to provide an overall estimate of visual-

motor ability. The WRAVMA Pegboard test was used to assess the child's fine motor skills

by requinng the child to insert as many pegs as possible into a grooved pegboard within 90

seconds. Each hand was tested separately, starting with the child's dominant hand. The

NEPSY Visuo-motor Precision subtest is a paper- and pencil test used to assess fine motor

skills and hand-eye coordination. It requires the child to draw a continuous line on a

cwilinear route as quicldy as possible. The NEPSY Design Copying subtest was used to

measure the chiid's ability to integmte spatial relational information with motor cosrdination.

This test nquires the child to copy NO-dimensional geumetrk designs using paper and pencil.

The presence of hand tremor and a qualitative description of the child's pencil grip was also

recorded. Finally, the NEPSY Imitating Hand Positions subtest was used to assess the child's

ability to reproduce a band position from a mode1 pmented by the examiner.

Visuo-spatial processing was assessed using the WRAVMA Matching, the NEPSY

Block Construction and the NEPSY Arrows subtests. The WRAVMA Matching subtest is a

paper and pend test that assesses various spatial skills such as perspective judgement,

orientation. rotation, and sue discrimination by presenting sets of pictures developmentally

arranged in order of increasing difficulty. The child was asked to indicate which of the four

options 'goes best' with the item standard. WRAVMA validity studies have shown that the

performance on the Matching subtest is more highly correlated with traditional tasks of spatial

skills (e.g. WISC-III Block Design, r=.61) than with verbal tasks (e.g. WISC-III

Comprehension, ~ 3 6 ) (Adams & Sheslow, 1995). The NEPSY Block Construction subtest

was administered to assess the child's ability to reproduce, h m models and pictures, block

constructions in three dimensions in a specified time limit. The child's score was deterrnined

by the number of correct constructions made. The NEPSY Arrows is a non-motor subtest

used to assess the child's ability to judge the direction, angularity, and orientation of lines.

The child was required to choose two m w s that point to the center ofa target fiom an array

of arrows.

Attention

Attention was assessed using the NEPSY Tower, Visual Attention, and Statue

subtests, as well as a vigilance Continuous Performance Test (CPT). The NEPSY Tower

subtest was used to assess the executive functions of planning, monitoring, self-regulation,

and problem-solving. It required the child to move three coloured balls to target positions as

quickly as possible according to a set of d e s . The Visual Attention subtest measured speed

and accuracy in scanning a linear or random array to locate a target picture which become

increasingly more complex with age. The NEPSY Statue subtest was used to assess the

child's inhibition and motor persistence. The task required the child to stand still in a set

position over a 75-second period while inhibiting responses (e.g. eye opening, body

movement, vocalization) to distracters. Lastly, a visuai CPT was used to measure the child's

vigilance (i.e. the maintenance of attention for infiequent but critical events over sustained

periods of time) which is thought to be closely regulated by arousal. The level of vigilance

was measund as the child's overall ability to identib targets correctly over the entire length

of the task. For children aged 3 to 6 years, the "Birdie in the Tree" CPT was used. This test

was a simple signal detection paradigrn where the children waited for a specified target item

to appear on a computer screen. The paradigm was explained in the context of a story about a

"silly tree" that had a nurnber of items in it that did not belong in the tree (cg. sailboat, fish,

train, telephone, etc.). The child's task was to press a telegraph key whenever a bird appeared

in the tree and resist pressing the key when other objects appeared. Children older than 6

years were tested with the C o ~ e n CPT (Corners, 1992), which required them to press a

teiegraph key each time a letter appeared on the screen and resist pressing the key when an

'X' appeared. Erron of omission and commission and mean reaction t h e were scored for

each CPT. Various modifications of CPT-type tasks have been used as laboratory measures

of attentionai problems, and false-alarm errors have been reported at increased levels among

hyperactive children and leaming-disabled, nonhyperactive childm (cited in Kopera-Frye,

Camichael Olsen & Streissguth, 1997). Furthetmore, performance on CPTs is correlated

with ratings of child impulsivity, organization, and endurance during the laboratory setting.

Women in the exposed group were dichotomized as having either a high or low

exposure to OS. Determination oflevel of exposure (high or low) was based on the woman's

exposure intensity (assessed using the weighted algonthm). Since the distribution of exposure

intensity was normal, exposure estimates greater than the median were categonzed as "high"

exposure, and scores less than and equal to the median were categorized as "low" exposure.

Women in the contrd group were entered into the analyses as having "no" exposure.

Statistical analyses were performed using version 6.12 of the Statistical Analysis

System package (SAS). Demographic data were analyzed with pararnetric and nonparametnc

tests depending on the nature of the measurement and the distribution. Discrete variables,

such as smoking and birth order, were analyzed with the chi-square test. Continuous

variables, including age, number of years of education and developmental milestones, were

assesseci with t-tests.

Control variables, including potential confounders and matching variables, were

analyzed using Pearson comlation coe~cients. The following variables were added as

covariates: age ofchild, gender of child, gestational age, age of rnother, yean of education,

socioeconomic status, smoking habits during pregnancy, and length of breast feeding. These

variables were prescreeneû based on the method describeci by Jacobson and Jacobson (1996)

to determine which to include in the multivariate anaiyses. This prescreening excludes

variables that are unrelated to the outcome so that the e m r tem is not reduced, thereby

improving the chances of detecting real toxic effects. Control variables were selected by

exarnining their univariate relations with each outcome. Al1 control variables that were at

least weakly related to the outcome being evaluated (at pc0.10) were considered as potentiai

confounders and were included as covariates in the analyses (see below). This pc0.10

criterion is conservative in this context because it includes even weak potential confounders.

Quantitative evaluation of the Minirnalist Test was done by caiculating the results of

both eyes (binocular score) and the mean results of the siagle eyes (monocular score) for each

child. The Wilcoxon-Mann- Whitney test (two-sided) was used to evaluate di fferences in

binocular and monocular chromatic discrimination between groups. LogMAR scores of the

visual acuity test were also analyzed using Wilcoxon-Mann-Whitney test. The relationship

between level of exposure and visual functioning was studied using a logistic regression

mode1 to determine whether there is a dose-level effect of the exposure.

To test the hypothesis of an association between prenatal solvent exposure and

performance on cognitive tests, exposed and unexposed groups were compared using unpaired

two-tailed t-tests (crude analysis). If an association was suggested by this analysis, multiple

regressions or analyses of covariance (ANCOVA) were used to assess the effects of solvent

exposure for each univariate effect. Covariates were determined separately for each

dependent variable based on a correlational analysis (see above). Al1 test results were

converted to z-scores on the basis of appropriate age noms. so that cornparisons between tests

could be made. Overall domain effects were analyzed by taking the average z-score for eac h

observation in each domain A toxic effect was inferred oniy if the relation between exposure

and outcome was significant at pcO.05 after controllhg for the confounding variables.


The collapsing of subtests within domains is bas& on considerations of test

inteicorrelations, and the nature of the tasks. The organization of the scores into domains

facilitates evahation of children's problems at relatively differentiated and more global levels.

This approach enables one to organize information in a systematic and useful way. It is then

possible to focus attention on syndromes of items found to CO-occur rather than dealing with

separate pmblems one-by-one.

Multiple regression analyses were perfonned using z-scores on each subtest as the

dependent variable and length of exposure. duration, symptomology, ventilation, and level of

exposure (hi&, low, or none) as the predictor (independent) variables. For each outcome

variable analyzed, the parameter(s) that accounted for the most amount of variance in the

mode1 was reporteci. Parameters which were predictive of outcome were interpreted to

indicate which dimensions of exposure (Le. length, duration, symptomoIogy. etc.) are most

strongly associated with the outcome measure. For al1 statistical analyses. the alpha level was

set at 0.05.

Prenatal Exposurc to Organic Solvents 3 1

Results

Results show that 70% of women who were successfully contacted and identified with

solvent exposure between 1992 and 1996 agreed to participate in the study compared to 76%

of the women in the control group. Appendix K provides information comparing the groups

on participation rates and on meeting the inclusion and exclusion criteria. Based on telephone

interviews, more pregnancies in the exposed goup resulted in miscarriage (6%) or

prematurity (4.5%) compared to the control group (2.5% and 2.5% respectively).

Table 3 shows the occupations and estimated solvent-exposures of the women who

were in the original cohort and of those whose children were evaluated in the present study.

The most cornmon occupations were iaboratory technicians, factory worken, and graphic

designers in boih the original and study cohort. in the original cohort, most women worked in

a factory (23%) followed by a laboratory (20%), whereas most women in the study group

worked in a laboratory (28%) followed by a factory (16%). However, the di fferences in type

of occupation between groups was not significant @=0.09). Chi-squared analysis showed that

more women in the original cohon were exposed to aliphatic hydrocarbons compared to the

women in the study cohort who were most frequently exposed to halogenated solvents

(p<O.OS). Because most of the women had exposures to more than one type of solvent,

analysis by type of solvent was not possible.

insert Table 3 about here

For both exposed and control groups, demographic and pregnancy-related information

about the women and their children is shown in Table 4. Six variables were used for

matching: gender and age of child, ethnicity, matemal years of education, socioecononomic

and marital status. To assess the effectiveness of matching, two-tailed t-tests or chi-squares

were performed on each matching variable. The mean Hollingshead score in the women in

the exposed group (M=43.28, m40 .73) was almost identical to the control women

(M=45.48, ==6.18), in the same socioeconomic stratum (medium business, minor

professional, technical), while the difference between groups was not significant, 1 (59)~-0.96.

9~0.32. Similarly, the groups did not differ in number of years of matemal education (1

(59)=0.78, p=0.44). Family cohesion, as measured by the FACES III, was rated as

"connecteci" for both the exposed (M42.60, ==3.74) and the control group (M=42.57.

==3.20) and no significant difference was found between groups ( ~ ( 5 8 ) = 0.049, p=0.975).

Family adaptability ratings, on the other hand, were slightly more toward the "stmctured"

range in the exposed group (M=24.47, ==7.39), compared to the control group who were

slightly more toward the "flexible" range (M=25.78, ==4.34). However, the difference

between groups in family adaptability was not significantly different (1 (58) = -0.821,

0=O.415).


Children in the control group were similar to children in the exposed group in almost

al1 demographic aspecis, except f ~ i more of their rnothers were older (L(59)=-2.44, H.03).

An approximate qua1 proportion of females and males were examined in each group. Groups

did not differ significantly on the number of days spent in the hospital after birth (i (56) -0.92,

p=û.36), gestational week at delivery (l(5 8)=O.M, g=û.73), child' s age at testing (1 (Sg)=O -92,

p=0.36), birth order (x2=( 1, N=61)=0.99, p=0.3 l), and matemal smoking during pregnancy

(X2=(1, N=6 1)=1.47,~=0.23).

The children's developmental milestones (as reported by the mother) are summarized

in Table 5. Results show that children of solvent-exposed women were not reportedly delayed

in walking (f ( 5 5 ) = -0.63, p=0.54), speaking first words (1 (46) = -1.74, p=0.10), or speaking

first sentences O (37) = -0.60, H.55). However, significant differences were found between

groups on age to crawl, f (40) = -2.47, p=0.02, and nui, 1 (42) = 3.16, pe0.01. Solvent-

exposed children were reported to crawl one month earlier (M=7.33, == 1.55) than children

in the control group (M98.77, ==2.60), but were later to run (M=19.83, SD=6.77) than non-

exposed children (M43.3 1, SD41.14). With respect to measures of growth, children of

solvent-exposed wornen were no more delayed than children of non-exposed women4.

Weight, height and head circumference measurements are summarized in Table 6.

Insert Tables 5 and 6 about here

Mother's ratings of their child's behaviour are reported in Table 7. With regard to behaviour

problems, no significant mean T-score differences were found between groups on any of the

CBCL narrow band scales [sleep pmblems (1 (14)==-0.08, fl.93). withdrawal behaviour (1

(58)=O. 17, p=0.36), sornatic cornplaints 0 (58)=0.37, p=0.07), anxiety (g (42)=0.97, p4.8 l),

social problems a (42)=0.43, p=0.54). thought problems (1 (42p1.80, ~=0.08), attention

problems (42)=-0.68, g=0.50), delinquenc y O (42)==.73, p=0.47), destructiveness (1


(14)=1.10, @.29), or aggressiveness (J (58)4.82, p=0.93)]. The groups also did not differ

on total problems [total problems (1 (S8)=1.85, p=0.07), intemalizing behaviours (1 (58)=1.79.

~=0.08), and extemalizing behaviours (58)=0.95, p4.35). The mean T-scores on the

CBCL were within a standard deviation of those expected for children in their age-group. It

should be noted, however, that there was a trend towards higher mean T-scores in the exposed

youp for all behavioural measures except for sleep and attention probiems. The higher scores

in the exposed group on the total problems and intemalizing behaviours likely reflects an

(non-significant) increased incidence of thought problems and somatic complaints.

Insert Table 7 about here

When the data were analyzed using a chi-square analysis, significantly more children in the

exposed group received a rating by their mother that was greater than the cutoff for borderline

behaviour (Le. T-score greater than 67) than in the control group (X' (1, N=6 1)=4.75, p=.03).

Figure 1 sumrnarizes the proportion of children per group who received a rating greater than

the cuto ff for borderline behaviour.

insert Figure 1 about here

The Minimdist Test scores were analyzed using the Mann-Whitney U-test because the

' Measurcs of bu<h weight were not comistentîy obtaincd for each chiid at the iime of follow-up and the~fore, are not rcported.


data were skewed and no transformations to a normal distribution were possible. Also,

nonpararnetric distribution fkee tests should be used when analyzing data fiom an ordinal scale

such as the Minimalist Test. Results were reported using the KrusKal-Wallis chi-square

approximation5. Results showed that the both binocular and monocular colour vision scores

were significantly higher in the exposed group for the protan (binocular: H4.52, 1, ~~0.03;

monocular: fi=l l . I l , 1, p<0.001) and tritan (binocular: U=9.34, 1, p<0.003; monocular:

B=10.72, 1, p<0.002), but not for the deutan (binocular: m . 1 4 , 1, p=0.05; monocular:

H=3.61, 1, p=0.07) colour conhsion lines. Figure 2 shows the mean binocular and monocular

insert Figures 2 and 3 about here

scores of the exposed and control groups for each colour confusion line. Tables 8 and 9 show

the fiequency of scores on the Minimalist test for exposed and control groups for binocular

and averaged monocular testing respectively. For a graphical representation, see Figure 3 for

Gequency of binocular scores for exposed and control groups on the Minimalist Test. In the

total sample, 2 out of 15 boys (1 3.3%) and 1 out of 17 girls (5.9%) in the exposed group were

classified as having a clinical red-green colour deficiency according to the limits of the

Minimalist Test compared to zero colour deficient children in the control group.

hert Tables 8 and 9 about here

Amoog the 33 childm in the cxpoecd group, 1 d e was excludcd because of congcnital colour blindness and 4 children r t k d to Wear the patch for testhg monocular colour vision, Among tbc 28 childrcn in the control group, 1 child fcll askcp for al1 visual tests and 1 child rehistd ta wciu the patch for testing rnonocular colour vision.

Prenatal Exposure to Organic Solvcnts 36

The relative risk of solvent-exposed males with rd-green color defects (1 3.3%)

compared with the incidence of males in the general population with such defects (8%) is not

significant (p4.50). However, it should be noted that the estimated 8% of males with red-

green color vision loss in the general population includes those with hereditary color vision

defects. It would be expected, therefore, that the incidence of males with red-green defects

would be less than 8% as we excluded those with known hereditary color vision defects.

Assuming a conservative estimate of 2% of males with a color vision defect not attnbutable to

a hereditary effect, the relative risk of color vision loss in the solvent-exposed males is 0.234

(95% CI: 0.065 - 0.842, pe0.03).

Logistic regression was performed to determine whether the presence of a colour

defect versus no colour defect could be predicted fkom exposure variables. B a d on the

explanatory variables included in our model, we could not predict the odds and probabilities

of having a colour discrimination defect. However, results of an ANCOVA showed that level

of exposure (hi*, low, or none) had a significant effect on the value of the log transformed

tritan score, E (2,55)=4.67, p4.01. ANCOVAs for the deutan and protan data showed weak

statistical evidence that level of exposure is nlated to colour discrimination.

Since no children in the study group wore glasses, al1 acuity scores represent

uncomcted vision. The Wilcoxon rank-sum test indicated that solvent-exposed children had

poorer binocular (M=0.07, m4.08) and monocular (M-0.10, ==O. 10) visual acuity than


children in the control group (binocular: M4.02, ==O.OS; monocular: M=0.05, m=0.06)".

Figure 4 shows the binocular and monocular mean visual acuity logMAR scores for the

exposed and control gmups. Although the differences are signi ficant (binocular: H=8.20. 1,

p<0.004, monocular: H4.47, 1, ~<0.034), acuity scores in the exposed group are within the

normal age-range and are not clinically significant.

Insert Figure 4 about here

Logistic regression was perforrned to determine whether visual acuity could be

predicted fiom exposure variables. Visual acuity of O logMAR (equivalent to 20120 vision)

versus acuity greater than O logMAR (Le. poorer acuity) were used as outcome variables with

level and length of exposure as predictor variables. Based on the explanatory variables

included in this model, we could not predict the odds and probabilities of having 20/20 visual

acuity.

Receptive and expressive language domain scores are summarized in Table 10.

Results showed a significant domain effect between groups on expressive language ability

0(59)=3.109, g=0.003), but not on receptive language ability ($(59)=1.632, p=O.108).

' Among tht 33 childrcn in the exposcd group, I maic was cxcludcd for a family history of visual defects and data fiom 2 childrcn were not included in the analysis because the confidence of the measurcmcnt was poor due to the childrcn jumping out of thcir scat to sec the card Mer . Another child in the exposcd group was excluded fiom the monocular visuai acuity analysis because he refiised ta Wear the eye patch. Arnong the 28 childrtn in the controt group, 2 childrcn were not included in îhe b i n d a r visual acuity analysis because the confidence of measwment was poor and another 2 were excluded fiom the monocular amlysis because they refuscd to Wear the patch.



Univariate results on tasks of expressive language are reported in Table 1 1. When

tests were anaiyzed individually using ANCOVAs, results showed a significant difference

between the exposed and control group on the EOWPVT-R with children in the exposed

group doing worse with adjustment for potential confounding factors, matemal age and

education, (E (1, 58) =5.83, pc0.02). Performance on al1 other expressive language subtests

did not differ significantly between groups [(Body Part Naming, (1 (35)=-1.66, p=0.08);

Speeded Naming, (1 (1 8)= 1.97, p-0.07); Verbal Fluency, (1 ( 5 6 ) ~ 1.26, p=0.2 1 )]. It should

be noted, however, that a trend in the results showed that chilâren in the exposed group

perfonned more poorly on most of the other tasks of expressive language compared to the

control group.

Insert Tabie 1 1 about here

On tasks of receptive language, no significant group differences were found [(PPVT-[II,

(1 ( 5 9 ) ~ 1.28, ~=0.20); Comprehension of Instructions, (1 (58)=0.77,9=0.44); P honological

hcessing, O (36)=-1.53, p=û. 1 S)]. Similar to the performance on tasks of expressive

language, a trend in the results showed that solvent-exposed children performed more poorly

on tasks of receptive language compared to the children in the control group. When the data

were analyzed by level of exposure (high, low, none) as the independent variable, results

reveaied a tendency for scores on the PPVT-III to get wone as exposure level increased,


adjusting for matemal education, E(2,57)=3.9 1, p=O.O3. Furthemore, mean scores for high,

low and no exposure differed significantly on Phonological Processing when age of child,

matemal education, and gestational age were used as covariates, E (2,33)= 1 7.68, p=0.02. No

dose-response relationship was found on the Comprehension of Instructions subtest.

Multiple regmsion analyses showed that some of the exposure variables were good

predictors of ianguage outcome as summarized in Table 12. Exposure variables were

signi ficantly related to Phonological Processing, Comprehension of Instructions, EO WPVT-R

and PPVT-III, but not on Body Part Naming, Speeded Naming and Verbal Fluency subtests.

For Phonological Processing, length of exposure (lu trimester versus full term) appeared to be

the best predictor of performance on with 27.82% of the variance accounted for by this

variable alone. The addition of the estimated exposure index into the model increased the

variance explained to 0.56 which is quite high. This hi& association between length of

exposure and Phonological Processing, E (2, 17)=9.75, p=0.002, is most suggestive of a

temporal-response relationship out of d l the outcome measures. For Comprehension of

Instructions, length of exposure, duration of exposure, and symptomology are al1 strong

predictors E (3,28)=6.40, p=0.002. On the PPVT-III, duation, ventilation and exposure

index were found to be the best predictors of outcome, E (3,29) = 6.48, g.0.002. Finally,

poorer performance on the EOWPVTR was associated with increased number of houn

worked per week, E (1,29)=5.33,@.03. The direction of the relationship was as predicted,

with poorer performance associated with higher exposure iniensity, longer length of exposure,

and increased fiequency of reported adverse effects. The exposure effects were described by a

hear model, meaning that prenatal solvent effects were estimated to Uicrease linearly.



Analysis of the visuo-spatial data revealed the domain effect was not significant between

groups. t(Sg)=-l.73. p=0.09. However. children in the exposed group showed a tendency to

perform more poorly on tasks of visuo-spatial ability than controls. Table 13 shows the mean

z-scores for the two groups. On individual tasks, significant between-group differences were

found on Block Constmction. E (3, 57)=3.36, p=0.025, adjusted for age of child and matemal

age. No effects were found on the Matching, 1 (58)=0.53,~=0.60 or Arrows, 1 (22)=-1 .OS.

~30.30 subtests. Multiple regression did not reveal any significant relationships between

erposure vari-ables and outcome measures.


Based on a factor analysis of the visuo-motor data, results were organized using 2

factors: fine-motor and graphomotor ability. On fine-motor ability, no overall domain effect

was founâ, t(59)==-0.06, p=0.95. On graphomotor ability, however, an overall domain e ffect

was found, t(59)=2.44, p4.02, showing pwrer performance in the exposed group. Table 14

shows the mean z-scores on tasb of fine-motor and graphomotor ability for exposed and

control groups. No significant between-group diffemces were found on univariate analyses

of fine-motor ability [Pegboard Test (dominant hand), (1 (59)=0.00,@.99); Hand Positions,

Rcnatal Exposure to Organic Solvents 4 1

(1 (53) =0.06, ~=0.95)]. On tasks of graphomotor ability, M O V A (adjusted for gender of

child, age of child, and matemal age) revealed significant between-group effects on the

Design Copying subtest, E (4,60)=3.85, g=0.01, and Visuo-motor Precision, E (2,60)=3.98,

g=0.024 (adj usted for gender of child).


Multiple regression analyses, as summarized in Table 15, revealed a tendency for

performance on both tasks of graphomotor ability, Design Copying and Visuo-motor

Precision, to get wone as exposure level increased. On both graphomotor outcorne measures,

the effects are described by a linear rnodel, with exposure variable values linearly associated

with deficits in ability. Poorer performance on the Design Copying was associated with

higher exposure intensity and fewer ventilation measures, E (2,29)=8.37,0=0.002, while

deficits on the Visuomotor Precision subtest were associated with increased length of

exposure and higher number of reported adverse effects, E (2,30)=4.74, p=0.02.

Insert Tabie 15 about here

Attention

Overall, the gmups did not differ in the attention domain, f (58)=O.CS, g=0.94.

Univariate analyses also did not reveai any significant differences between gmups [Statue, (1

(55) ~ 1 . 2 2 , ~30.23); Visuai Attention, @ (53) =1.50, fl.14); Tower, (t (22) 4.67,

Prcnatal E q o m to Organic Solvents 42

g=0.5 l)]. Mean z-scores on taslrs of attention are provided in Table 16'.

lnsert Table 1 6 about here

' The d t s of tûe "Budie in the tm" CPT arc not pesented as part of this paper bccaux the scoring for this meamire has yct to be established- Conner's CPT rmilts are not reportcd as part of this paper because the numbcr of children complcting this task was too d. Rcsults of these îasks will bc part of a subsequent publication.


Discussion

The intent of this study was to investigate the effects of maternai occupational

exposure to OS on visual and cognitive development in the offspring. The specific locus of

the study on visual huictioning was prompted by past studies on animals and adults showing

that the visual system may be especially vulnerable to solvent exposure. Based on ihis

vulnerability, we hypothesized that prenatal exposure to OS wouid disnipt visual development

and result in long-terni perturbations in colour vision and visual acuity. Given the assurnption

of an underlying dysfunction of the visual system, chiken exposed to OS in urero were

expected to show deficits on tasks of visuo-spatial and visuo-motor ability. Prenatal exposure

to OS was also predicted to disnipt language and attention because exposure during a cntical

period of brain development may affect emerging cognitive huictions. Finally, it was

hypothesized that higher doses and increased length of exposure to OS would be associated

with more pronounced deficits in visual and cognitive functioning.

The results of the present study provide support for the first hypothesis that matemal

occupational exposure to OS during pregnancy is associated with adverse effects on their

chilci's subsequent colour vision and visual acuity. The colour vision deficits that were found

among the solvent-exposed group were mainly of the tritan (blue-yellow) category suggesting

evidence of an acquired dyschromatopsia. Interestingly, clinical red-green colour vision

deficits were identified in 3 children in the exposed group compared to O in the referent group.

On tasks of cognitive hctioning, mild deficiencies were detected in expressive language,

block construction, and graphomotor ability. The observed deficits on block construction and

graphomotor ability provide tentative evidence of an impairnent to the visual system that may

subserve these abilities. At the present the , however, it is t w early to interpret where in the


brain neurobiological changes occurred. The approach used in this study was largely

clinically based using standard tests of visual and cognitive hctioning. Further research

using neurochemical, anatomical and neurophysiological methods is needed to guide this

work and find information about the effects of prenatal solvent exposure on brain

development .

The central finding of this sîudy is the increased number of colour vision deficiencies

in children exposed to OS Ni utero. Of particular interest is the greater incidence of tritan

(blue-yellow) discrimination deficiencies in the solvent-exposed group than the control group.

This discovery presents preliminary evidence of a solvent-induced neural alteration in prenatal

visual development. The possibility that the deficit was inherited is unlikely since defects in

the tritan pigment are not sex-linked and very few people have an inhented blue-yellow

defect, occumng equally in both sexes in about 0.002 to 0.007 percent of the population

(Pokomy, Smith & Vemest, 1979). Furthemore, past studies have shown that blue-sensitive

cones are generally more susceptible to toxic substances than red- and green-sensitive cones

(Mergler, Bélanger, Grosbois & Vac hon, 1 988). Given the rarity of tritan de fi ciencies in the

general population, our finding provides strong support that prenatal exposure to OS may be

associated with an acquired colour vision deficiency. This observation is consistent with the

acquired blue-yellow colour vision loss reported in adults exposed occupationally to OS.

The pmsent findings are also of clinical importance with respect to rd-green clinical

colour discrimination deficiencies. Even after excluding al1 children with a family history of

colour vision defeets, we identified 2 out of 15 boys (1 3.3%) and 1 out of 17 (5.9%) girls in

the exposed group with a clinical rd-green colour deficiency compareci to O children in the

Prenatal Exposure to Orgaaic Solvents 45

control group. This is a very high prevalence when compared to the general population where

the incidence of red-green colour blindness is 8% for males and 0.4% for females (Pokomy et

al., 1979). The incidence of colour blindness in the general population would be even less

when cases with a family history of colour vision defects are excluded as in our sample.

Although the red (protan) and green (deutan) type of congenital colour vision deficiencies

could have been transmitted by a recessive X-linked mode of inheritance by the mother, the

probability of this happening is equally likely to occur in both groups. These findings

therefore suggest that prenatai solvent exposure may be linked to an increased incidence of

acquircd colour vision defects.

Poorer chromatic discrimination among solvent-exposed children was found despite

precautions that should have minimized group differences. Specifically, al1 children who

were believed to be at greater risk of showing abnomal visual development due to a farnily

history of heritable retinal disease or congenital colour vision loss were omitted from the

analyses. Ail children were tested by the sarne penon to reduce any variation in test

administration. To ensure adequate visual acuity, al1 chilâren were prescreened for normal

acuity for their age (see Appendix 1 for the logMAR chart used to determine normal acuity).

The subject groups were well matched on age and gender, and no significant differences were

found in performance by age or gender. Finally, it is unlikely that the deficits in chromatic

discrimination were due to cognitive diffaences between groups because minimal cognitive

and attentional demands were required by the Minimalist Test. To ensure adequate

comprehension of the test instructions, the examiner did not begin testing until the child

succeeded on the pretest.


in children exposed in utero to OS, we do not yet know where dong the complex

network of interconnecting neurons of the pnmary visual pathway the impairment resides.

Because similar effects on colour vision have been reported in adults exposed to OS. it is

suggested that similar pathways or systems may also be disrupted by prenatal solvent

exposure in the fetus during visual development. According to Koilner's nile, most blue-

yellow defects appear in retinal disease and are believed to occur at an eariy stage in visual

dysfunction of optic neuropathy; red-green defects, on the other hand, mostly appear in optic

nente disease and are associated with more severe optic neuropathy (Hart. 1987). Since an

increased incidence of chromatic discrimination impairments were found on al1 colour

confusion lines among children exposed to OS in utero, our findings may reflect changes to

both retinal layers and optic nerve.

Some hypotheses can be made on the specific mechanisms involved in the neuro-

ophthalmotoxicity ofprenatal exposure to OS based on research findings of past studies.

Blain et al. (1994) perfomed electroretinographic measurements on rabbits chronically

exposed to tricholoroethylene (TRI) and found that its metabolite trichloroethanol (TCE)

modifies retinal physiology. They suggested that the retinal changes caused by chronic

exposw to TRI increases the penneability of Miiller cells to extracellular potassium,

enhances the axonal transport, and potentiates the retinal doparninergic system. It is possible

that prenatal exposure to OS also interferes with the retinal dopaminergic system resulting in

alterations in the neural Functioning of retinal cells and / or optic pathways. Although other

studies support the idea that alterations to dopamine levels in eariy life can impair visual

bctioning (e.g. Diamond & Herzberg, 1996), ihis hypothesis should bc m e r explored.


e of a Dose- or T

The fhdings showed that colour discrimination capacity for the blue-yellow range was

worse for the high exposure group compared to the low and no exposure groups. This dose-

response relationship led us to examine whether children with the most severe colour vision

defects (Le. complex dyschromatopsia in both the Mue-yellow and the red-green range) were

associated with high levels of exposure. interestingly, the results did not show a dose- or

temporal-response relationship between exposure level and seventy of colour discrimination

impairment. Only one of the three mothers of children identified as having a clinical red-

green defect was exposed to a hi& level of OS (refer to Appendix J, Case History 1 for a

description of the mother's exposure history), whereas the other two were categorized as

having low exposure to OS during pregnancy (refer to Case History 2 and 3, Appendix J).

This discrepancy suggests that clinical colour vision loss may occur even when the mother's

exposure is low and asymptomatic dunng pregnancy. It should also be noted that the

observed cases with clinical colour vision impairment were not associated with a speci fic

occupationa or type of solvent.

As predicted, the solvent-exposed group showed a trend for poorer performance on

most subtests compared to the reference group, and chilchen in the low exposure p u p did

somewhat better than children in the high exposure group. Significant differences were

detected on selective tasks of expressive language, visuo-spatial and graphomotor ability. The

' Mn. X (Case History 1) hPd the highcst exposuce. She worked in a printing factory and was prllannly exposed to mcthyl cthyl kctonc (MEIC). MIS. Y (Case History 2) worked as a lab technician in a paint factory and was exposed to ammatic hydroc;ins, alcohols, ME.K and complex solvcnts. Mn. 2 (Case History 3) worked as a chemist and was exposcd to halogenated compounds, alcohols and to a lcsscr extcnt, aromatic hydrocarbons.

Prtnatal Exposurt to Organic SoIvents 48

reason that most tests did not attain statistical significance may be because of the srnall sarnple

size a d o r because the effects 010s are typically subtle raising questions of adequate power

in this study. Our findings are sirnilar to those of other studies on workers occupationally

exposed to OS in that differences are relatively mild and cover a variety of mental fictions.

Even though the cognitive deficits fond in this study were subtle, they are relevant to the

assessrnent of whether neurodevelopmental deficits occur, and the evaluation of the relation

between dose and response. However, in evaluating the results, the limitations of the study

should be considered.

. . cts on A b u

An overall domain effect of prenatal exposure to OS was observed on expressive

language but not receptive language. Since early developmental characteristics are suggested

to be early indicators of later functional development (Kenemaekers et al., 1997), we

predicted that the observed deficit in expressive language would correlate with a delay in age

to speak first words or use first sentences. However, this was not the case; the solvent-

exposed children acquired use of first words and sentences at the sarne age as the reference

group. The discrepancy between the observed deficit in expressive language but not in

language milestones can be explained by one of Kennard's (1 940) early observations: "that

certain behavioral impainnents do not occur immediately after early brain damage, but

emerge only later in development, at a t h e when the relevant behavior would normally

appear" (cited in Dennis, 1988, p.97). What Kennard proposed, in essence, was that a lesion

in early development may produce relatively few irnmediate problems, but that durhg later

development, the lesion may cause the young brain damaged organism to "fail to acquire"

(Kennard, 1940, p.388, cited in Dennis, 1988) a skill.


Convergent evidence of a targeted effect of prenatal exposure to OS was observed on

tasks of graphomotor ability. Results showed that solvent-exposed children perfonned

significantly worse on the Design Copying and Visuo-motor Precision subtests even d e r

statistically adjusting for a variety of potential confounding variables. Furthemore. a dose-

response cffect refiected poorer graphomotor ability with increasing exposure level. One

proposed reason for this specific impairment may be related to an underlying dysfunction of

the visual system. Ifearly exposure to OS results in structural malformations of the visual

system, this may lead to less efficient integration of visual information with higher-order

processes. Further studies should explore the hypothesis that early damage to some portion of

the pnmary visual sysiem may contribute to reduced input to the undarnaged area.

Evidence of a Ternooral-Re- of Pr- tto Or& S o l v w

It is well known that "susceptibility to teratogenic agents varies with the

developmental stage at the time of exposure" (Wilson, 1977, p.50). This pnnciple of critical

periods in behavioural teratology divides susceptibility to prenatal damage into periods

depending on their degree of vulnerability. Generally, these periods are termed:

preimplantation, organogenesis, histogenesis, and functional organization. Our attempt to

explain the variation in cognitive outcome as a huiction of critical periods was for the most

part not very fruitful. It appears that exposure does not have to span the entire pregnancy for

suhtle defi&nc#9 to be detected in the offspring, suggesting that maximal sensitivity to OS

occurs during kt-trimester organogenesis in humans. increased teratogenic vulnerabili ty of

the brain during organogenesis has also been shown with other teratogens including

antimitotic agents, vitamin A, neuroleptics, anticonvulsaats, akohol, opiates and irradiation

Prcnatal Exposwe to Organic Solvcnts 50

(Shepard, Fantel & Mirkes, 1993; Vorhees, 1986).

For the most part, the results of the current study support the concept suggested by

Wilson (1977) that the susceptibility of neurotoxic insult generally dirninishes with advancing

development. interestingly, the Phonological Processing subtest was the only task that

showed a strong temporal relationship between outcorne and length of exposure. This task.

which consists of sound blending and word completion, is unique because it was the oniy one

that depended highly on hearing ability. The heightened sensitivity on the Phonological

Processing subtest rnay pnsent evidence of a longer period of increased vulnerability of the

developing auditory system. Although the auditory system is believed to mature somewhat

earlier than the visual system, there are data to suggest that the developing auditory system is

still subject to injury even in the perinatal period (reviewed in Rodier, 1994). The auditory

system's critical period of development, therefore, may span a longer period compared to the

visual system. Moreover, evidence that OS can induce hearing losses cornes Frorn past studies

in rats (Nylén, Hagman & Johnson, 1995; Loquet, Campo & Lataye, 1999). Based on

electrophysiological and histological data, Loquet et al. showed that styrene and toluene can

cause auditory threshold shiAs in mid (16 kHz) and mid-low (4 Hz) Frequency regions, while

high styrene concentrations are capable of causing fiequency-independent hearing losses.

Although the evidence of a hearing impairment associated with Full tenn exposure to OS is

preliminary, hture studies should include hearing and auditory processing tests as part of a

hi11 clinicd examination of neurotoxicity.

It is largely unknown why fetal teratogenic effects are not always seen in children after

apparently similar prenatal exposure. Our hdings revealed high variability in the magnitude

Prenatal Exposure to Organic Solvents 5 1

of effects in children, even though their mothers were exposed to the sarne OS under similar

conditions. This variability most likely reflects a combination of factors, such as differences

in metabolic rate, timing of exposure during pregnancy, or interactions with other variables

known to affect exposure such as smoking and alcohol.

Although the dose and timing of prenatal exposure explains some of this variability,

inter-individual variability as to when the effects may manifest is another possibility .

Children with similar exposures may show different effects due to an altered dynarnic

plasticity in the brain. This brings up an interesting philosophical question of whether a more

legitimate route to understanding the cognitive effects of prenatal solvent exposure lies in

studies that do not involve averaging across subjects. Mer all. it was this motivation for the

case study method that gave rise to the prominent cognitive neuropsychology research of

language that began about 25 yean ago (Goodglass & Wingfield, 1998).

Before the deficits can be attributed to prenatal solvent exposure, some

methodological considerations need to be discussed. Fintly, valid cause and effect inference

can not be drawn based on this type of research design because random assignrnent and

expenmental control over extraneous influences are not possible. The matched cohon design

is limited because it can not tell the tnie impact of the matched variable nor does it assure that

cases and controls were comparable in al1 respects. Although it wouid be ideal to match

children and women on every possible variable that could afFect performance, this is not

possible in research with humans. Thus, control For confounding is a primary concem for this

type of study and alternative explanatioas for obsened effects must be carefully evaluated.

Prenatal Exposwe to Organic Solvenis 52

Secondly, the study of behavioural teratology is complicated by the difficulty in

reliably estimating the dose of exposure in the mother and the fetus. Assessrnent of solvent

dose of exposure in the mother is dependent upon many factors that may have an effect on

reproductive outcome or may possibly interact with the effects of solvent exposure. In

quantifjmg dose of exposure, environmental variables (e.g. ventilation. temperature, duration

of exposure), characteristics of the individual (e.g. body weight, physical rxercise), as well as

effect-modifying factors such as smoking, alcohol consumption, the intake of drugs, and

exposure to other chernicals must be taken into account. The study of behavioural teratology

is m e r complicated by the difficulty in reliably assessing the dose of exposure absorbed by

the fetus. Thus, the calculated index of exposure employed by this study should serve only as

a crude estimate of actual exposure. It should be noted that an unreliable estimation of dose

may have given rise to misclassification of exposure level which, in tum, wouid have diluted

the effects of the exposure.

Another caveat in this study is the problem of accurate estimation of maternal solvent

exposure. Women's exposure to OS was estimated based upon their response to a series of

standard questions asked by a counselor at the time the woman contacted Motherisk dunng

her pregnancy. Not only is this method of exposure estimation crude, but the accuracy of the

estimated exposure index is dependent upon the woman's report. This method raises

questions of reliability because exposure information reported by each woman may Vary

depending on her familiarity with the chernicals or her anxiety over the pregnancy. For

example, a wornan who is highly concerned about the exposure may falsely attribute a feeling

of nausea due to the exposure when in fact it was an effect of the pregnancy. Thus, maternal

Prenatal Exposure to Orgaaic Solvents 53

report of exposure variables may not be useful in predicting outcome because any true

relationship may be diluted by invalid reports.

As part of this study, it was of interest to see how well women could recall

information about their occupational exposure dunng pregnancy. Materna1 recall of exposure

information could differ from the information reported at the time of the pregnancy due to a

matemal reporting bias, or an impaired memory resulting from the solvent exposure. X

cornparison of the exposure information obtained from the mother at the time of pregnancy to

that obtained at the time of the study is shown in Appendix L. Not surprisingly, the data show

large discrepancies with respect to reports oE duration of exposure, bamers used during

exposure, and whether symptoms were experienced upon exposure. One way in interpreting

these discrepancies is that there was a bias in retrospective ascertainment of exposure. But as

discussed above, even prospective matemal report cm be inaccurate. Nevertheless,

quantifjing matemal occupational exposure to OS through interviews may not be the most

reliable method of obtaining the information. These discrepancies need to be examined in

much more detail to detemine when the bias was greatest and why this rnay be so. Further

studies should explore the validity of using matemal report of occupational exposure in

behavioural teratology studies.

Another methodological consideration is in the interpretation of the CBCL results.

The CBCL showed that matemal reports of problem behaviours were considerably more

common among mothers in the exposed group than among mothers of the reference group.

This result could be due to a tendency in exposed women to rate theu chilàren as having more

pmblem behaviours compared to the refmt gmup. Women in the exposed group are more

likely to ahbute problem behaviours to the occupational exposure because they are biased by

Prenatal Exponirr to Organic Solvcnts 54

the exposure and they know their child is being tested for this reason. In order to understand

the real meaning of the difference in materna1 ratings of child behaviour, the children need to

be re-rated by another source such as a teacher.

The selection of the exposed group should also be considered when interpreting the

subtle differences between groups. One reason why the differences were subtle may be due to

the conservative selection OF the exposed group. The sample of c hildren in the exposed group

were regarded as a low-risk group because only full-term, physically n o m 1 children were

included. Children who were bom prematurely were excluded because of the possibility that

an observed relation between exposure and outcome could have been a spurious consequence

of gestational age. As prematurity is also a likely adverse consequence of prenatal toxic

exposure, we have restricted ourselves to the hardier population including those more resistant

to the effects of solvent exposure. Future studies should include children who were bom

premature by matching children for gestational age and using it as a mediating variable in the

relation of prenatal exposure to OS to developmental outcome.

Age at testing is another important variable in the interpretation of results in

behavioural teratology studies because outcome may Vary depending on the age of childe. The

choice to study young children between the ages of 3 and 7 was based on the lact that early-

age cognitive assessments of behavioural teratology outcome may be more sensitive than tests

in older children because of recovery processes and potential bbcatch-up". Functional recovery

fiom teratogen-induced CNS damage can occur by: neural reorganization, compensation or

substitution by brain areas less affectai by the exposure (cited in Hannigan, 1995). Since any

- -

9 Ideally, we would have Likcd to study an cvcn more restricted age mgc, but this could not be achievcd due to a smaii sample size.


or al1 of these recovery processes rnay be operating while the brain is still early in

development, neurotoxic effects may be exacerbated or ameliorated later on in development.

Therefore, we chose to investigate the effects of prenatal solvent exposure in young children.

However, the selection of young children, as opposed to older children, rnay also have

its shortcomings. Brain damage in urero has widespread potential for sorne degree of nsk tor

abnomal onset, rate of mastery, control and up-keep of each and every cognitive ski11

developed over the life span. According to Dennis (1988), the damaged developing CNS

should be viewed as a dynamic plastic system in which teratogenic outcomes are expressed as

processes of recovery. She argues that dysfunction is more likely to change its expression

over development than to disappear. For example, the onset of a skill rnay be delayed, but

once the skill is mastered, it rnay be less than what would normally have been projected. For

this reason, a follow-up in the children at an older age rnay yield variable, long-term sequelae

of early damage that were not detected at an early age. Thus, it is possible that neurotoxic

effects do not become evident until a later age, when complicated cognitive skills such as

reading begin to emerge.

A major limitation of this study is that the expenmenter was not blinded to the condition

of the childtO. It must be achowledged that an examiner who is aware of the child's condition

rnay bias the administration or the scoring of the tests. It is believed that experimenter bias in

the present study was more likely to have affected the results of the neuropsychological than

the vision tests because the response variables on the vision tests were less apt to be

'O Blinding was aot a d is t ic consequence of this research projcct due to the time and energy coostraints of a Masters projcct.


infiuenced by the experirnenter. This study attempted to decrease this bias by having a

blinded observer score the results of any subjective tests, including the Design Copying and

the Visuo-motor Precision subtests. Also, the three other examiners who tested approximately

20% of the children were blinded to condition.

Another limitation to the study is the selection of the exposed group. Because a

number of children h m the original smple were lost to follow-up, the exposed group cm

not be regarded as representative of the onginal sample. It should be noted, however, that

factors reflecting cases lost to follow-up (e.g. moving, changed phone numbers) were not

expected to systematically influence scores. The reader should also be cautioned that the

sample of mothers in the exposed group is not representative of ail pregnant women who work

with OS, and may in fact represent a more mildly affected group. Mothen who took the

initiative to contact the Mothensk program during their pregnancy are more likely to be more

conscientious about chernical exposure, and therefore may have taken greater precautions

against solvent exposure (i.e. used protective equipment, minimized length of exposure) than

the general population of exposed pregnant women. As a result, the exposed group in this

study may have inadequate exposure levels to produce noticeable neurobehavioural deficits in

their offspring.

Finally, due to the smail number ofwomen exposed to a particular type of solvent or

solvent c h , it was impossible to isolate the various OS and examine the effects of each

separately. This is a limitation of this study because it is well known that certain classes of

OS have different effects than others (Mergler, 1998). For example, aromatic hydrocarbons

are highly opthalomotoxic and rnay rapidly affect the optic nerve more so than halogenated

Prenatal Exposwe to Organic Solvents 57

solvents or alcohols. By grouping al1 types of OS together in the analyses, we can not specify

which are more h m h l types of solvents.

Our findings offer exciting new questions for hiture research* As mentioned above, one

particularly important area bat needs to be fùrther studied is the effects of prenatal exposure

to a homogeneous class of OS. This is critical bccause information about specific effecrs of

OS will help determine which types of occupations are at increased risk of neurotoxicity.

Forthcoming studies should work closely with health officiais who can provide reliable

measurements of exposure to OS dunng the tirne of pregnancy. Ideally, quantitative measures

of solvent concentration in ambient and expiratory air, or measures of metabolite excretion in

the urine must be obtained at the time of pregnancy in order to establish reliably a dose-

response relationship for particular solvents.

In addition to neuropsychological tests, neurophysiological techniques such as visual

evoked potentials (VEPs) or electroretinograms could be used to investigate more directly

nervous system functions that may be additionally impaired. Not only do these techniques

serve as objective and reliable methods of evaluating neural activity, they cm also provide an

unprecedented o p p o d t y for linking brain lesion with outcorne. Research using

electrophysiological strategies is critical for linking neurotoxic darnage to brain structure and

fiinction.

Clearly, more research examining the efiects of prenatal exposure to OS is necessary

for determining the long-terni effects of early exposure over the lifespan. Long-term or

subsequent follow-ups on these children should be performed with tasks involving greater

cognitive demands as well as a variety of other areas (e-g. memory, anthmetic). Furthemore,


effects of prenatal exposure to OS should be compared with the effects of prenatal alcohol

exposure as a starting place. M e r all, alcohol is a soivent, and studies on toluene abuse have

show similar effects as those found in fetal alcohol syndrome (Pearson et al., 1994).

Research should examine whether deficits resulting fkom materna1 occupational exposure to

OS resemble deficits found in children with alcohol-related birth defects. By using

biobehavioural markers of neurotoxicity found in the vast number of audies on prenatal

alcohol exposure, we cm get evidence of whether the nvo exposures share a similar

pathology. If there is an association between these exposures with respect to pathway

disniption and neural deficits, Our undentanding of the effects of prenatal solvent exposure on

the developing CNS may potentially be advanced much laster than previously thought.

This investigation provides unique insights into the effects of OS on the developing

CNS. Our findings suggest that prenatal exposure to OS may be related to subtle alterations

in ce11 proliferation or migration during early CNS development. The results of this study are

also relevant in Furthering our understanding of the extent of visual development before birth.

For instance, an analysis of the time of exposure and the presence of a colour vision

deficiency cm yield information about the organogenesis of the visual system's components.

Further research in this area will advance our understanding about critical periods in

neurodevelopment.

The importance of routine screening following neurotoxic exposure in young children

is emphasized based on the results of the present study. By using quantitative measures of

visual and acoustic ability, subtle effects of neurotoxic exposures rnay be detected early in

life. This is important because knowing that a cbild bas a visual or acoustic deficit may

Preoatal Exposure to Otganic Solvents 59

facilitate the child with respect to Iearning and adaptation. For exarnple, if a teacher is aware

of a child's colour discrimination deficit, the use of colour as a teaching tool may be avoided.

Furthemore, leaming can be facilitated by helping a child with colour vision defects learn to

use other cues to detect colour differences or by altenng visual displays to be more visible.

Finally, if research shows a trend of an increased risk of visual and / or neuropsychological

impairments among solvent-exposed children, health professionals, such as cyc carc clinicians

and child psychologisrs, will be better equipped to detect and diagnose the dyshuiction in

early childhood. It will also be critical For specialists to inquire about prenatal exposures

when deficits are suspected in children.

Our tindings show an increased Rsk of adverse effects on visual and cognitive

development following matemal occupational exposure to OS dunng pregnancy. Although

the findings of the present study do not signim causality, the discovery provides suppon for

an important working hypothesis that matemal occupational exposure to OS during pregnancy

is associated with "subclinical" deficits (i.e. cognitive and visual deficits in normal

intelligence children that would not necessarily be evident in an informa1 clinical

examination) in the offspring in the absence of physical malformations. Until replicated,

however, these findings should be treated as preliminary. We conclude that it is worthwhile

to Collow-up chilàren exposed to OS in utem, even when the level of exposure is low and the

degree of deficiency is mild. With further research in this area, we can hope to identify what

particular OS are most h a r d 1 and what level of exposure is not teratogenic. Understanding

the risk of matemal occupational exposure to OS will have implications for potential

interventions of teratogenic exposures and will heîp establish safety guidelines for pregnant

women exposed to OS at their workplace.

Prenatal Exposun to Organic Solvent6 1

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Table 1

Block Test

1 NEPSY Subtests:

Body Part Naming

Design Copying

Phonological Processing

Comprehension of Instructions

Visuo-motor Precision

B lock Construction

Statue

Verbal Fluency

EOWPVT-R

WRAVMA Pegboard test

WRAVMA Matchhg test

PPVT-III

Continuous Performance Test

Cardiff Cards

Minimaiist Test

Table 2

BIock Test

NEPSY Subtests:

Design Copying

Tower

Arrows

Speeded Naming

Phonological Rocessing

Comprehension of Instructions

Visual Attention

Visuomotor Precision

Statue

EOWPVT-R

WRAVMA Pegboard test

WRAVMA Matching test

PPVT-III

Cardiff Cards

Minimallst Test

Continuous Performance Test

Table 3

Occupation

Factoq worker l Machine operator

Laboratory worker 1 Technician

Graphic designer

Dry Cleaner

Ph0 tograp hic development

Artist 1 Art teacher

Chemist

Cat prep Uidustry 1 Paint plant

ûperating room penonnel 1 ûccupat. Therapist

Solvent Exposure

Halogenated Solvents

Aliphatic Hydrocarbons

Aromatic Hydrocarbons

Complex Solvents

Alcohols

Aîdehydes

Glycols

Table 4

Women

No. of years of education

Hollingshead Score

Age at delivery * No. months breast-feding infant

Mother breast-fd infant (%)

Smoked cigarettes (%)

M d e d at follow-up (%)

C hildren

Gender (% female)

Gestational week at delivery

No. of days in hospital after birth

Child's age (yrs) at testing

Birth Order: First bom (%)

Mer Demographic uiforrnation

Live in d a n environment (%)

FACES-pl Cohesion Score

FACES-III Adaptability Score

Ethnicity: North Amencan (%)

Table 5

Begin to Crawl * 7.33 1.55 29 8.77 2.60 26

Begin to Walk 12.71 2.60 3 1 13.31 4.14 26

Begin to Run ** 19.83 6.77 23 14.38 4.22 21

Speak First Words 13.00 4.30 26 15.91 7.12 22

Use First Sentences 20.88 6.41 24 22.20 7.08 15

Table 6

Males Growth

Weight (ibs) 46.04 10.87 15 44-64 6.73 13

Height (cm) 109.53 9,95 15 111.18 9.33 13

Head circurnf. (cm) 52.96 1.12 15 52.15 1.24 13

Fernales Growth

Weight (lbs) 41.99 8.52 t 6 42-97 6.34 14

Height (cm) 107.75 9 3 16 110.38 9.25 14

Head circumf. (cm) 5 1.63 1.42 16 51.23 1.94 14

Table 7

Narrow Band Syndromes

Sleep Problems

Withdtawn

Somatic Cornplaints

Anxious 1 Depnsseâ

Social Problems

Thought Pmblems

Attention Problems

Delinquent Behaviour

Destructive Behaviour

Aggnssive Behaviour

Intemalizing h b l e m s

Extemalking Problems

Total Probtems

Prcnatal Exposurc to ûrganic Solvents 8 1

Table 8

* Incrcasing score rcflects gratter chromatic discrimination dtficit

Table 9

Score * Exiipppd

Deutan Protan Tritao Deutan Protan Tri t an

* Increasing scotr tcflects p a t e r chromatic discrimiaation dcficit

Table 10

Sc- for

Receptive Language 0.338 0.738 0.627 0,626 -1.632 59 0.108

Expressive Language O. 173 0.685 0.696 0.728 -2.889 59 0.005

Visuo-spatial Ability 0.020 0.797 0.375 0,802 -1.727 59 0.089

Fine-motor Ability -0.13 1 0.779 -0.1 18 0,788 -0.063 59 0.950

Graphomotor Ability -0.450 0.993 -0.149 0.905 -2.442 59 0.018

Attention 0.349 0.709 0.336 0.595 0.076 58 0.939

Table 9

Subtcst

Receptive Language

PPVT-IF 0.309 0.849 0.588 0,844 -1.282 59 0.21

Comprehensioa of Instructions 0.542 0.798 0.702 0.828 -0,765 58 0.45

Phonologicd Processing 0.167 0.964 0.611 0.802 -1.534 36 0.11

Expressive Language

Speeded Naming -1,167 1.199 -0.100 1.228 -1.965 18 0.07

EOWVT-R 0. 188 1 .O00 0.843 0.880 -2.692 59 0.01

Body Part Naming 0.400 0.746 0.843 0.883 -1.655 35 0.1 1

Verbal Fluency 0.469 0.780 0,782 1.107 -1,262 56 0.21

Prcnataf Exposurc to Organic Solvents 85

Table 10

Variable

Phonological Processing 0.57 9.78 0.002

Length -1.50 0.41 -3.61

Exposure Index -0.32 0.10 -3.62

Comprehension of Instructions 0.43 6.38 0.002

Length -0.61 0.27 -2.23

S ymptom -0.40 0.15 -2.65

Duration -0.50 0.28 -1.77

PPVT-III

Ventilation

Exposure Index

EO WPVT-R

M. "Lcngth" rcftrs to a wcightcd d u c with high values rcpresmting fiiU tcrrn cxposurc, "Symptomn reftrs

to the nuniber of adverse cfftcts asmciatcd with solvcnt cxposurc during pregnancy, "Duration" refers to a

weighted value rcpmcnting number of houn worlccd pcr wctk, "Exposwc Index" rcprescnts the intcnsity of

exposure assigncd to tach woman calculatcd using an algorithm of weighttd factors known to affect dose of

cxpo-.

Plenatal Exposure to ûrganic Solvcnts 86

Table 11

Subtest

WRAVMA Matching Test 0.42 1 0.964 0.555 0.999 -0.528 58 0.60

B lock Construction -0.323 1.043 0.310 0.968 -2,440 59 0.02

~ O W S -0.077 0.818 0.273 0.800 -1,054 22 0.30

Prenatai Exposurt to Olganic Solvents 87

Table 12

Subtest

Finemotor Skiils

Hand Positions -0.471 0.884 -0.487 1.088 0.060 53 0.95

Pegboard Test (dominant hand) 0.202 1 .O8 1 0.202 1 .O32 -0.001 59 0.99

Graphomotor Skills

Design Copying -0.091 1.191 0,548 1.187 -2.090 59 0.41

Visuo-motor Precision -0.808 1.014 -0.250 0.996 -2.159 59 0.04

Prcnatal Exposure to ûrganic Solvents 88

Table 13

Variable

Design Copying

Ventilation

Exposure Level

Visuo-rnotor Precision

Length -0.93 -0.93 -2.88

S ymptom -0.29 -0.21 -1.39

Table 14

Subtest

Statue 0.462 0.713 0.166 0.855 1,424 55 0.16

Tower 0.615 0.837 0.364 1,005 0.670 22 0.51

Visual Attention 0.062 1.116 0.405 0.650 -1.437 59 0.16

Prcnatal Exposure to Organic Solvcnts 90

Problem Behaviour

Pimiatal Exposurc to Otganîc Solvents 9 1

Binocular Monocular

2 - B. Monocular

Colour Confusion Line

Binocular Monocular

Prcnatai Exposure to Organic Solvents 94

RESEARCH INFORMATION

Date of Blrth:

HSC #:

Matemal Occupational Exposure to Organic Solvents During Pregnancy and Subsequent Visual and Cognitive Development in the Child: A Prospective Controlled Pilot Study.

Christine Siambani, BSc. Research Coordinator, University of Toronto, Dept. of Psychology (416) 813-7654 ext. 4343

Dr. Joanne Rovet, Ph.D. Professor and Senior Scientist Dept. of Psychology, University of Toronto Dept. of Psychology, The Hospital for Sick Children Phone: (41 6) 8 13-7442

Dr. Cideon Koren, M.D. Director and Professor Div. of Clinical Pharmacology and Toxicology, The Hospital for Sick Children Phone: (416) 813-5778

Many women are exposed to solvents in workplace settings, such as laboratories, factories, or the printing industry. The purpose of this study is to study the relationship between minor occupational solvent exposure during pregnancy and children's early developrnent. At pcesent, most information about the effects of solvent exposure cornes h m studies in adult workers. It may be possible that chilcûen whose mother's were exposed to solvents have different rates of developmmt than children whose motha's were wt exposed to solvents. We feel it is important to snidy whether this relationship exists. In this shidy, we want to see if children of mothers exposed to solvents are able to solve problems in attention and verbal ability at a level appropnate for their age. Also, we want to see if these children have normal colour vision and other skills related to the visual system that are appropriate for their age. Research in this area is important to understaad the nlationship between solvent exposure duriag pregnancy and children's development.


Appendix A Continueci

This study will compare a group of 3 to 7 year old chilchen whose mother's were exposed to solvents with a similar group of children whose mother's were not exposed to solvents during pregnancy. Children will be asked to corne to the Hospital for Sick Children for a 2 hour testing session (includiiig breaks). We will test colour vision, visual acuity, attention, verbal ability, fine motor skills, and spatial abilities. Most tests involve participation in a game-like situation where the child is asked to point to objects or copy picnim.

Although we expect no h m , your child rnay experience some discornfort being in a new situation and an unfarniliar setting. Also, it rnay be an inconvenience to get to the Hospital for Sick Chilàren or to find t h e in your schedule to participate in the snidy.

It would be beneficial to be aware of any colour vision loss a child rnay have for several reasons. Firsf howing a cbild experiences colour problems would help the teacher understand any difficulties the child rnay have in learning. Second, if a child is aware of this impairment, he or she will be able to l e m to use other cues to detect differences among colours. It should be noted that if colour vision loss is suspecteci, a refenal to an eye doctor for m e r examination will be provided.

In addition, the test battery will give you information about your child's ability on specific tasks of attention, verbal ability, fine motor skills, and spatial abilities. Upon completion of the study, you will receive a report descniing your child's results which rnay be usehil in later educational planning. If a problem area is identified, we will share this information with you, and provide recommaidations for improvement.

Society in g e n d also benefits h m your participation in this study. Doctors will be better able to aâvise mothers who are exposed to organic solvents at their workplace on any potential risks to her baby. This rnay help d u c e anxiety among pregnant women, and rnay mult in counseling opportunities for fiinire pregnancies. Lastly, research in this area rnay have implications for changes in workplace regulations for pregnant women.

Confidmtiality will be respectecl and no Uiformation that reveals the identity of you or your child will be released or published without your consent. The resuits of the tests described above will be used for research purposes only in the context of this study. We would need your permission and signed consent to send these test scores to another professional involved in your care. For your information, the research consent fonn will be inserted in the patient health record. We recommend that the results of these tests be interpreted by a registered psychologist or physician.

We will nimburse you for any transportation andor parking costs that are incurred b y participating in this study.

Participation in research is voluntary. If you choose not to participate, you and your family will continue to have access to quality care at HSC. If you choose on behalf of your child to participate in this sîudy you can withdraw your child fiom the sîudy at any time. Again, you and your family will continue to have access to quality care at HSC.

If you wouid like to know the source of fuading, please discuss this with any of the investigators: Christine Siambani at (41 6) 8 13-7654 ext. 4343, Dr. loanne Rovet at (4 16) 8 13-7442, or Dr. Gideon Koren at (416) 813-5778.

Appendix B

RESEARCH CONSENT FORM

Date of Birth:

HSC #:

1 acknowledge that the research procedures described above have been explained to me and that any questions that 1 have asked have been amwered to my satisfaction. 1 have been informai of the alternatives to participation in bis stuciy, including the nght not to participate and the right to withdraw without compromishg the qudity of medicd care at The Hospital for Sick Children for my child and for other members of my farnily. As well, the potential harms and discornforts have been explained to me and 1 also understand the benefits (if any) of participating in the research study. 1 know that 1 may ask now, or in the htwe, any questions 1 have about the study or the research procedures. 1 have been assured that records relating to my child and my child's care will be kept confidentid and chat no information will be nleaseâ or printed that would disclose personal identity without my permission unless required by law.

1 hereby consent for my child to participate.

The Person who may be contacted Narne of Parent about the research is:

who may be reached at telephone #:

Signature 3-7654 a 4343

Name of person who obtained consent.

Signature

Date

Appmdix C

Outcome of Follow-up

- - -

No. of women iost to follow-up 52 44.4

Women contacted 65 55.6

Women who w m excludeci at time of screening

Woman removed h m exposure 3 4.5

Women exposed to other chernicals 2 3 .O

Non-occupational exposure to solvents O O

No. of women with endocrine dysfunction 2 3 .O

No. of women with depression 1 1.5

No. of non-English speaking fimilies 1 1.5

No. of women with neurologicai abwrmality O O

Pregnancy les than 36 weeks 1 1.5

Pregnanc y resulted in rniscaniage 4 6.0

No. of children who were not testables+ 1 1.5

No. of women sent uiforrnation 50 42.7

No. of women agreed to participate ' 35 70.0

No. refiscd to participate 15 30.0

No. of woman who missed appointment 2 4.4

Total no. of children teste& 37 33

Reasons why children were excluded after testing:

Child uncwperative O O 2 6.1 '

Child bom premahue ( 0 6 weeks) 2 5.4 1 3 .O

Family history of visuai defects Ob O 1 3 .O

Complication during pregnancy 1 2.7 1 3 .O

Maternai use of recreational dnigs 1 2.7 O O

Total no. of children included in study 33 28

Each wonitn was sckctcd as a potential coniml based on theu cxposurc information obtaincd at the time of

pregnancy. ûniy women and their chiidrm who matchcd a pair in the exposcd group werc asked if thty wcrc

interestcd in participating.

+* one autistic child (expostd); 1 child witb cpilcpsy and 1 child with leukania (controls)

* calculatcd as a petcentagc of women who wete sent Uiformatioa

' of the 37 exposed chiidrtn, 4 wem siilings; of the 33 control childrcn, 8 were Jiaihgs

calculatcd as a pcrccntage of womcn who wert sent idonnation

one chüd with congcniîai colour vision los was excluded h m the visual fùnciioning tests child fell aslccp and

1 child was hypctactive and did not complete mort tban half the tests

PaUent's N m t

Hom phwc Workphont

D e of b i i Amnio? Y& No0 Advisedo

Memdby: H c r l t h d #

Stable Conw # nrliriwlila:

Currcrit MDJtype= pa0ne:

OccuMli011:

NOT PREGNANT gcami UiCoO P-8 0 ietrospbctiv~0 b r r u t f i g o

(-1 evuy &ys Ccrcrin? Y N

Cumfy: weight kg lb gtrtrtion wk moi

cm byd-oby-0

iNCûMING: date: thne

counseuoc

compIcktî 0 passcd LO leUow0

OUTGûiNG: date: tinte:

completcd b y

-Y No0 Ycs Hmt No0 Ytr

Hyputamioa N o 0 Yer

Di&eîcs No0 Yca

R ~ ~ ~ w c Y N o 0 Ycs

Tbymid N o 0 Yes

Psychurric N o 0 Ytr

epicpry No0 Ytr

Vi~supplemeaution? No0 Yu:

Oi&r

-w ! WRMQpslaricy 4

I Cocaine, Crack- m m ~ ~ VW-W

Marijuana -(rrqug

m r : DURM(3Rlirrr 1

O Chlamydia OChiclrcn port O W t a l h e r p e s mononhea OCortsaclQe ~Hepatitis B OHLV OParvovinis B 19 OSyphiüs O Vm"alla mtr.

Type of contact: oblood Odiycue of& Obouschold Ohospitai Owiîb lesions O mucoul 0 d orexwl O*

Patient had disease in the past 0 Distase ciinidy d i a g d ? Ng) Yeso by

Refercaced advice +box on pg. 1

C)icmicrl: Occupation: ,Y

Referenced advice + box on pg.1

Numkr of times brcostfed daily: how often?

Date of birth: Gestational age at birth: wk Birth weight: kg lb F o r m a supplemeatption? Yes No Solids? Yes No

name w Am you taking mcdication as p d b e d ? age stnrted age starttd Yes No # timeslday U t i d d a y

Th6 infonnation is confidential and for professional use only. Please fill out as completely as possible.

Name of child: Date of bùih (ciMy):

Name of pmou completing fom:

Mother's Namt: Biological Fatheis name:

Address: Addrtss: check if same as mother [ ]

Home phone:

Work phonc:

Age:

Occupation:

Highest grade complctcd:

Home phone: samc [ ]

Work phone:

Age :

Occupation:

Highest grade completcd:

Language spokcn most 0 t h at homc:

Eutopean Paternai ethnlcity: [ 1 European Afncan [ 3 Alkan North Anmîcan [ ] North AmCncan Asian Indo-Asian

[ 1 Asian [ j Indo-Asian

1 Latin [ 1 Latin l Wei. (specisr) [ 1 (specisr)

Marital Statur: Marricd [ ] Scpmted [ ] Divorccd [ ] Widowcd [ ] ûthtr [ 3 Namt of petson who spenâs most timt with child:

Do any other miatives livc at homc? Please dcscrik.

Please describe reasons for medication, details about medical condition and the name of the prescn'bing physician for any medication taken during pngaaacy.

Dnig Namt Caicndar start date Calendar stop date Drug dose Route

B. Job J

1.

2.

3.

Occupation during pregnancy:

[ ] ongoing txposurc

j ongoing cxposurc

[ 1 ongoing cxposum

Length of ernployment at h e of pregnancy:

v o ~ o c c u m : [ ] physical effort [ ] mental concentration / attentional demands [ ] repetitive motion [ ] manuai dextetiîy [ ] time pressure

* . e: [ ] expoexposed to irritants such as dust and other chernicals [ ] high temperature or hmidity in workplace [ 1 Poor üghting [ ] loud noise [ ] cmwding [ ] shift hours worked

Date returned to work after pregnancy:

Name of chemical(s) exposed to during pregnancy @leuse indicote which exposure(s) are prinrary (in same area where chemical used) and secondury (indirect exposure):

Start date of exposure: [ ] present at start of gestation [ ] other (specib)

Stop date of exposun: [ ] specify number of months pregnant: months [ 1 other (specify)

Duration of exposun: [ l h r s l d a ~ x - number of days per week

Ventilation during exposure: [ ] none [ ] fumehood [ ] general - wdl & roof fan, ceiling vent [ ] natuni1 - open windows & door

Barrien during exposure: [ ] gloves [ ] apmn, helmet [ 1 mask [ 1 go~gies [ ] respirator [ ] other

Could you, or other empioyecr, smeU or taste cbemical vapors during work? [ ] no [ ] yes

Side e f f i t s during exposure: [ ] none [ ] visuai irritations [ ] diarrhea [ 1 rash [ ] dininess [ 1 na- [ ] headache [ ] (spe~i@)

hnatal Exposure to Organic Solvents IO5

Appendix E Continued

Alcohol [ ] No [ ] Yes How many drinlrs? per [ ] day [ ] week [ ] month

Date alcohol co11sumption stopped: when pregnancy diagnosed [ ] Addi tional information:

Cigarettes [ ] No [ ] Yes How many? per [ ]day [ ] week

Date tobacco exposure stopped when pregnancy diagnosed [ ] Additionai information:

Recreational Drags: Please describe type(s) of h g , fiequency of use, and at what month of pregnancy use was stopped (if applicable).

Was the father taking any medications or dmgs at the tirne of conception? if so, what?

Anaestheda duringpregnancyng y [ 1 No [ 1 Yes type: date@) of exposure:

Radiation during pregnancy [ ] No [ ] Yes type: date(s) of exposure:

Did you have any injuries during your pregnancy? [ ] No [ ] Yes Please explain type of injury and when it occumd.

Appenâix E Continueci

Kidney Heart disease Diabetes Epilepsy Hematologic Hypertension Psychiatric Neuro logic Respiratory Thyroid disease Vitamin supplementation Other (speciQ)

Do you Wear glasses? N [ ] Y [ ]

Is the biological mother colour blind? N [ ] Y [ ]

1s the biological father colout blind? N [ ] Y [ ]

Do you have a family history of acquired or congenital colour vision loss? N [ ] Y [ ]

B. w ' s M-

Name of family physician I pediatrician who has pnmary care of child:

Doctor's address:

Date of child's last physical exam:

Please describe any periods of ihess or hospitakation (injuries, accidents, operations, convulsions, allergies, ear infections, etc.)

Has your child had his / her vision checked? [ ] no [ ] yes I f yes, by whom? Date: Finding : Glasses: [ ] no [ ] yes

Has your child had any special medical examinations (Le. neurological)? [ ] no [ ] yes Please specify.

Does your child take any routine medication? [ ] no [ ] yes

Curent medication:

What for?

Cumnt medicai problems:

C* Pmaiaev

Length of pregnancy (in weeks):

Any illness or complications while pregnant? [ ] no [ ] yes

tf yes, please explain:

D* - Was the biith of the child 'normal'? [ ] no [ ] yes Infant home at days.

Ifno, please explain.

Was your child bom: [ ] mahue [ ] prematurr (less than 36 weelrs)

Appendix E Continued

Requirement of resuscitation or nanatal interisive care unit? [

Problems following birth (please describe):

Brest feeding [ ] no [ ] yes aonle feeding [ ] no [ ] yes

started at days stopped at days started at days stopped at days

crawl:

fed self with spoon:

used single words:

potty trained / day:

waik alone:

scribbled:

used sentences:

potty ûained / night:

ran well:

tied shoes:

Does your child have any language difficulties? [ ] no [ ] yes

Please describe:

Do you see the child as being [ ] hyperactive? [ ] inattentive? [ ] a behavioural problem?

Please explain:

Prenatal bposurc to Organic Solvcnts 109

IV. I f 1 or- . .

Nail biting

Thumb sucking

Bed wetting

Sleep problerns

Tantnuns

Abnormal aggressiveness

Pronounceci disobedience

Destnictiveness

Overactivi ty

Pst [ 1 present [ 1 past [ ] present [ ]

past [ ] present [ ]


past [ ] pnsent [ ]


past [ ] present [ 1 past [ ] present [ ]

Pst [ 1 present [ 1

Name of sibling(s): Age Sex Grade Live at home?

How are sibling nlationships? [ ] good [ ] fair [ ] poor

G* * P lease add any additional comments you think might be helphil.

Signature: Date:

Relationship to child:

Inunkpu for tuking the rime to compfete th& form.

Appmdix F

Social Shta for the Hollingsheod Four-Facor Inder ofSociocconomic Statu

Social Strata Range of Computed Scores Level

Major business and profcssional 66 - 55

Meâium business, minor professional, technical 54 - 40

Skilled craftsmen, clencal, sales workea 39 -30

Machine operators, semisicilleci workers 29 - 20

Unskilled laborers, menial service workers 19-8

Appendix G

FACES III

David H. Olson, Joyce Portner, and Yoav Lavee

1 2 3 4 S ALMOST NEVER ONCE iN AWHILE SOMETiMES FREQüENTLY . ALMOST ALWAYS

DESCRIBE YOUR FAMILY NOW:

Family mtmbcrs ask cach other for help.

In solving probltms, the childrcn's suggtstions arc followed.

WC approve of each othcr's f r i tnds

Childrcn have a Say in thtir discipline,

We likt to do things with just our immediate family.

DiTferent persons act as leaders in our family.

Family membtrs Ceel clostr ta other family members thrn to people outsidc the f'amily.

Our family changes itâ way o f hondling tasks.

Family memben tikc to spend frcc time wifh each other.

Parcnt(s) and children discuss punishmcnt togethcr.

Famity membcn fetl very close to each othtr.

The childrcn makc thc decisions in our family.

Whcn our family gets togcther for activities, cvcrybody is prescrit.

Rulcs change in Our Tarnily.

WC can easily think of things ta do togcthcr as a fnmily.

WC shift household rcsponsibilities from pcrson to pcrson.

Family membcrs consult othcr family mcmbers on thcir decisions.

It is hard CO idcntify thc lcodcr(s) in our family.

Family togcthcrncss is vcry importan t,

It is hard to tell who does which household chorcs.

FAblILY SOCIAL SCIENCE, 290 ~ c ~ c a i Hall, University a l Miiirrita, St. Paul, hlN 55108

@ D.H. Olson, 1985

Appendix H

Ranges of FamiS, Adaptability and Cohesion Evaluation Scala (FACES)

Family Cohesion Range of Scores Family Adaptability Range of Scores

Disengaged IO- 34

Separated 35 -40

Connected 41 - 45

Enmeshed 46 - 50

Rigid 10 - 19

S tnictured 20 - 24

Flexible 25 - 28

Chaotic 29 - 50

Appendix 1

Test Pmtocol for Young Children (aged 3-4 years)

Verbal Ability

NEPSY Body Part Narning Naming of body parts depicted on a picture

NEPSY Phonological Processing Sound blending and word completion tasks

NEPSY Comprehension of Instnictions Process and respond to verbal instructions

NEPSY Verbal Fluency Ability to generate words within a category

EOWPVT-R Naming of objects depicted in line drawings

PPVT-III Receptive language test; Predictive of verbal I.Q.

WRAVMA Pegboard Test

NEPSY Visuo-motor Precision

NEPSY Design Copying

NEPSY Imitating Hand Positions


NEPSY Block Construction

Attention

NEPSY Visual attention

NEPSY Statue

Insert pegs into a grooved pegboard within 90-sec.

Draw a continuous line on a curvilinear route

Drawing two-dimensional geometric designs

Ability to reproduce a hand position h m a mode1

Identification of picnins conesponding with test item

Assembly of blocks to replicate 2D representations

Measms speed and accuracy in locating a target

Ability to stand still in a set position over a 1 1 5 sec.

Mollon-Refi-Miriirnalist Test Measures colour vision discimination

Cardiff C d Acuity Test Assess visual acuity using high fkquency test

Appendix J

Test Protocof for Children (uged 5-7years)

Verbal Ability

hTPS Y Phonological Rocessing

NEPSY Spcaded Naming

NEPSY Verbal Flumcy

EO WPVT-R

PPVT-III

Visuo=Motor AbIUty

WRAVMA Pegboard Test

NEPSY Imitating Hand Positions

NEPSY Visuo-motor Precision

Sound blending and word completion tasks

Assess aaming ability; rapid access to and production of

narnes of recufnng colors, sizes, and shapes

NEPSY Comprehmsion of lnsüuctions Process and respond to verbal instructions of

incnasing syntactic complexity

Ability to generate words within specific categones

Naming of objects depicted in line drawings

Receptive language test; Redictive of verbal I.Q.

Numba of pegs inserted within time limit

Ability to reproduce a hand position h m a mode1

Ability to draw a continuous line on a curvilinear

mute as quickiy as possible

NEPSY Design Copying Drawing two-dimensional geometric designs

Domain Description

VisuoSpatial Procesrhg


NEPSY Arrows

NEPSY Block Construction

Attention

NEPSY Tower

NEPSY Visual attention

NEPSY Statue

Vlruai Functioning

Minimalist Test

Cardiff Acuity Test

Identification of pictures which correspond wiîh test item

Judge Üne orientation and directionality

Assembly of 3-D blocks to replicate 2-D

representations of designs

Assess nonverbal problem-solving abilities

Measures speed and accuracy in scanning an

anay and locating a target

Ability to stand still in a set position over a time

period while inhibiting response to distracton

Assess chromatic discrimination capacity

Assess visual acuiîy

ueparrrnenr or upnrnainioiogy Visuaf EIectrophysioIogy Unit Carof Westall PhD

Name: Cardiff Acuity Norms ,,,: *' 6 95 % lirnits Date:

Date fEye Tested

Age (months)

+Log MAR Acuity Score

Card : 1 2 3 4 5 6 7 8 9 10 11

2 rnetres 0.3 0.4 O. 5 0.6 0.7 0.8 0.9 1 .O 1.1 1 .2 1.3

Binoc O Test Distance Card giving Acuity Hm it Confidence?

O=lowest; 1 O=highest

Appenâix L

Case History: Maternai Occupational Solvent Exrposure In formation

According to the information provideci to us, Mrs. X was worked as a machine

operator in a printing factory for the full terni of her pregnancy. Her work involved physical

effort, mental concentration, repetitive motion, manual dexterity, and tirne pressures.

Conditions at her work hclude exposlne to chemicals, high temperature, poor lighting, loud

noise, and crowding. Mm. X had been employed at the factory for 7 years pnor to her

pregnancy with Joshua Mrs. X had inhalation exposure to methyl ethyl ketone (MEK),

silicon, and ink strippers, up to 10-hours a day. 4 days a week. She did not use any

protective barriers and her workplace was ventilated only with nahiral measures (Le. open

windows and a door). Mrs. X could detect the chernical fumes and she complained of

numemus adverse effects including dizziness, headache, visual irritations, nausea, trouble

breathing, and mucousal buming. She stated that she felt her symptoms were worse than

those of her workplace colleagues. Mrs. X retumed to her employment as a machine

operator approximately 10 months after Joshua was bom.

Appenk L Continued

According to the information pmviâed to us, Mrs. Y was working as a laboratory

technician in a paint factory for the full term of her pregnancy. Mrs. Y had been working in

the colour-mstching room as a colour fomulator for approxirnately 4 years prior to her

pregnancy. Her office was separateci by a closed door from a larger room where paint and

solvents were mixed under fume hoods. Adjacent to that area was a larger area where the

production and testing of the paints occurred. Mrs. Y sometimes tested products in the spray

booth which was in this larger ana. On average, she worked 6 hours a day, 5 days a week.

Mrs. Y provided Motherisk with a fairly extensive List of chemicals. Some of the major

chemicals she worked with include: toluene, xylene, lacquer solvent, naptha, varsol, methyl

ethyl ketone, acetone, ethanol. aicohols, isocyanates and epoxies. Mrs. Y wore gloves,

protective clothing, a respirator, and goggles when handling the chemicals. Although she

could detect organic solvent fumes and an ammonia srnell, Mrs. Y did not report any adverse

effects upon exposure to the chemicals.

Prcuatal Exposurc to ûrganic Solvcnts t 19

Appendix L Continued

According to the information provided to us, Mrs. Z was workhg 7.5-hour shifts, 5

days a week, as a sample coordinator chemist for the full temi of her pregnancy. She

perfonned quality assurance testing which required physical effort, mental concentration,

repetitive motion, manuai dexterity and time pressures. Although Mrs. Z handled the

chemicals under an adequate fumehood ventilation system, she could still srne11 the chemical

hunes. She used protective bamiers including gloves, a lab coat, goggles, and a mask and

respirator when necessary. Mn. Z fbquently workeâ with acetonitrile (1-2 hodday x 3-4

d/wk), acetic acid (2 xlwk), methanol, butanol, ethanol, chlomform, hexane, perchloric acid,

hydrochloric acid, and sodium hydroxide. To a lesser degree, she also worked with pyridine,

toluene, ammonium hydroxide, and tetrahydrofuran. Mrs. Z did not report experiencing any

adverse effects upon exposure to the chemicds.

Appendix M

Matemal Report ofExpomre Information Obtained ut The of Pregnancy (before)

and ot Time of Sludy (1 999).

* Duration refm to the number of hours per week

o Burkn refers to the numkr of protective masures used upon exposure to the solvents - Side effects refen to the numkr of adverse symptoms eXpenenced upon exposure to solvents

of · analysis of the data. ... case history report fom. ... 1 995; hooisma, hanninen, emmen &...

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