studies of kidney cancer and pcbs

8/3/2019 Studies of Kidney Cancer and PCBs

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Studies of Kidney Cancer and PCBs

The following 29 studies show the possibility that PCBs increase kidney and

urothelial cancer risks. This may not be a complete list of all kidney cancerresearch related to PCBs. For more, visit the TOXNET database operated by

the National Library of Medicine (the source of these abstracts). Keep in mind

that these kidney cancer studies are not all equal in size or quality. Some were

published in peer-reviewed journals, while others were simply presented at

conferences. A few are duplicates by the same author (one conference-based,

another published) but we presented both because the descriptions were

slightly different.

Study #1

PCB exposure produced a consistent increase in kidney cancer

A review by researchers from the National Institute for Environmental Health

Sciences used an analysis of combined occupational studies, and concluded that

PCB exposure produced a consistent increase in kidney cancer, although the

actual number of cases was small. (Longnecker et al, 1997)

Study #2

higher numbers of kidney cancer for men followed PCB exposure

In January 1985, following a period of high electricity demand, an electric

transformer located in a residential building basement and containing PCBs

exploded in Reims. This led to the dispersion into the building of

polychlorobiphenyls (PCBs) and trichlorobenzene from the inside of the

transformer and the dispersion of PCB thermic breakdown products, especially

furans (PCDFs) and dioxins (PCDDs). 343 people were exposed : firemen,EDF (French government-owned power company) workers, residents of the

building and visitors. A medical follow-up was organised until 1990 when it

was suspended due to a poor participation. However, it had to resume in 1994,

due to health problems observed in personnel who had intervened during the

accident. The RNSP (Public Health National Network) was commissioned by

the Ministry of Health to make an epidemiological survey. Among the most
http://toxnet.nlm.nih.gov/http://toxnet.nlm.nih.gov/


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frequently reported symptoms within the highly exposed group of people (75

people), important losses of memories, fatigue, itches and skin allergies have

been noted. The study of cancer incidence revealed higher numbers of breast

cancer for women, kidney cancer for men. This accident led the French

government to strengthen the existing legislation on PCBs: 1975: An order on

behalf of the Public Health Code restricted the use of PCBs and rendered their

disposal mandatory after use. 1983: An order on behalf of the Labour Code

relating to labelling and packaging for hazardous substances was issued. PCBs

were classified as noxious substances. 1985: Total ban on further installation

and use of equipment containing PCBs. 1987: Mandatory disposal of all

equipment containing more than 100ppm. Despite this, the 96/99/CE European

Directive relating to PCBs and PCTs disposal has only been made French law

in January 2001, and only after France has been rebukby the European

Commission for not respecting deadlines set for the inventory phase for

contaminated equipment and failing to present a disposal scheme. (Cordier et

al, 1996)

Study #3

machining fluids [including PCB-containing pyranol] were

associated with kidney cancer

A case/control study was carried out of cancer associated mortality at a

transformer assembly factory in Massachusetts. Seven types of exposure with

mutagenic or carcinogenic potential were rated together with the operations in

which they were used. The chemicals were pyranol (1336363), benzene

(71432), trichloroethylene (79016) (TCE), mixed solvents, machining fluids,

asbestos (1332214), and synthetic resins. The cohort consisted of 1,821 white

male subjects with 51,063 person years of employment. Site specific cancer

deaths were regarded as cases, and comparisons were selected from deaths

considered unassociated with any of the exposures. Odds ratios (ORs) were

calculated. Results showed that 28 exposure/cancer associations could be

identified as important in the binary exposure regressions or in the contingency

table screening. Pyranol lymphomas and solvent oral/laryngeal/pharyngeal

cancers showed a greatly reduced association, whereas a consistent positiveassociation was evident between benzene and brain tumors, other solvents and

lymphomas, and resins with lung cancer. Regressions with multiple exposures

were also computed. A modification of the induction latency analysis method

was used, and the only notable finding was an association between machining

fluids and kidney cancer. Associations of resins with rectal and lung cancer,

machining fluids with kidney cancer, and TCE with leukemias seemed to be


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largely or entirely concentrated to post 1950 exposures. Cross tabulation

showed a similar association between level 2 solvents and reticulosarcoma. The

authors conclude that the link between machining fluids and kidney cancer is

new, and that this as well as a possible association between lung cancer and

resin systems deserve further investigation. (Greenland et al, 1994)

Study #4

kidney cancer was reported in three utility workers exposed to PCBs

Primary unifocal renal adenocarcinoma was reported in three caucasian male

utility workers exposed to polychlorinated-biphenyls (PCBs). The first was 34

years old with a 5 year history of extensive unprotected PCB contact as a

painter in a transformer repair shop. The second was 43 years old, with a 14

year history of exposure to PCB oil as a linesman, and the third was 56 years

old, with 8 years work history as a painter in a transformer repair shop. None ofthe cases reported any personal risk factors, although they had histories of

occupational exposures to organic solvents, herbicides, electromagnetic fields

and PCBs. Pathological examination of the tumors showed solid cell sheets

with eosinophilic cytoplasm and some cuboidal cells (first case), solid cell

sheets with mostly clear cytoplasm and a prominent vascular component

(second case); and clear cells in sheets as well as tubular and alveolar

structures, accompanied by a moderately dense inflammatory infiltrate (third

case). Traces of herbicides and pesticides and their products, but no PCBs,

were found in sera of the first two cases. The second case reported a chloracne

like rash. The authors conclude that electrical utility workers are exposed to a

variety of chemical and physical agents, and recommend an epidemiological

investigation of renal adenocarcinoma in this industry. (Shalat et al, 1989)

Study #5

deaths caused by kidney cancer increased significantly with

increasing exposure to pentachlorophenol [contaminated with dioxin

--- certain PCBs are dioxin-like]

The cancer risks associated with pentachlorophenol (87865) (PCP) exposurewere examined. Work history records were used to form the study cohort of

770 employees of Dow Chemical Company in Michigan. Industrial hygiene

and process data were used to evaluate PCP exposure. A modified life table

approach allowed for the estimation of expected deaths and the calculation of

standardized mortality ratios (SMRs). While 242.5 total deaths and 52.6 deaths

caused by malignant neoplasm were expected, observed deaths totaled 229 and


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50, respectively. A significant excess of deaths caused by gastric or duodenal

ulcer was observed, with an SMR of 357. The prevalences of death caused by

kidney cancer, gastric and duodenal ulcer, cirrhosis of the liver, and all

accidents increased significantly with increasing exposure. Although the excess

in lymphopoietic cancer deaths was not significant, a trend toward higher risk

with higher PCP exposure was evident. However, a significant number of

deaths was observed in the low exposure group, as well as in the groups

exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (1746016) and other

benzodioxins. The authors conclude that this study does not support the

possibility that PCP exposure increases the risk of liver and adrenal gland

cancers. Workers may have incurred an increased risk of death due to some

specific causes, but may have been associated with some factor other than PCP

exposure. (Ramlow, 1996)

Study #6

PCBs demonstrate increased risk of urothelial cancers [ includes

kidney cancers]

Classification of workers' exposure status by combinations of occupational title

and industrial category, or job/exposure matrix, was used on census data to

identify chemicals carcinogenic to the lower urinary tract. Fifty chemical

compounds were chosen on the basis of prior identification as definite or

probable urinary tract carcinogens. The exposed group was chosen from

occupations in which at least 10 percent of persons in the job category had

estimated exposures during the census year of at least 1 hour per week to any of

the selected compounds. Those in the remaining occupational groups were

assigned to the unexposed group. Links between exposures and work tasks

were constructed, and the positive predictive values for each link were

characterized. Analysis was restricted to the 1,905,660 employed males aged

20 to 64 years as of 1960; the observation period was from 1961 to 1979. Cases

of urothelial cancer were identified through the Swedish Cancer Registry. A

total of 556,429 were assigned to the exposed group. Exposure to creosote

(8001589), chlorinated phenols, and phenol (108952) judged as low to

moderate in predictive value was found to increase the risk of bladder cancer(relative risk (RR) 1.8) and renal pelvic cancer (RR 2.6). Exposure to some

lubricating oils and fluids caused slight increase in the RR. Chemical process

workers with exposures to unspecified aromatic amines were showed to be at

increased risk of bladder cancer. Exposure to polycyclic aromatic hydrocarbons

caused increases in the RR, dependent upon the source of combustion gases.

Other substances demonstrating increased risk of urothelial cancers were


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chlorinated aliphatic hydrocarbons and polychlorinated biphenyls. (Steineck et

al, 1989)

Study #7

PCB pretreatment increased the protein binding of another kidneytoxicant and carcinogen (Tris-BP)

The nephrotoxicant and nephrocarcinogen tris(2,3-dibromopropyl)phosphate

(Tris-BP) is activated to products which bind covalently to microsomal protein

by a cytochrome P-450 dependent oxidation reaction. Binding to rat liver

microsomes proceeds 15 times faster than with kidney microsomes. The

binding in liver microsomes is markedly increased by phenobarbital

pretreatment, the apparent Vmax of the reaction is 175 pmol/mg microsomal

protein/min with control microsomes and 1053 pmol/mg protein/min with

induced microsomes. Binding with kidney microsomes is doubled afterpretreatment with polychlorinated biphenyls. 2,3-Dibromopropanol (2,3-DBP),

a hydrolysis product of Tris-BP, is also activated to covalently protein-bound

products, but at a much slower rate than Tris-BP. Administration of Tris-BP to

rats leads to its covalent binding to proteins in liver and kidney, with 5 times

higher binding levels in kidney than in liver, correlating with its relative

organotoxic potential in single dose experiments. Binding to proteins in the

kidney was increased by pretreatment of animals with polychlorinated

biphenyls. A covalent interaction of Tris-BP with DNA could be demonstrated

when DNA was added to liver microsomal incubations in vitro and to DNA

extracted from liver and kidney after administration of Tris-BP in vivo. The

binding levels were 4 times higher to kidney DNA than to liver DNA.

(Soderlund, et al, 1981)

Study #8

PCBs promoted the production of nodules

adenocarcinomas of kidney were composed of clear cells arranged in

solid, alveolar patterns

The effects of polychlorinated biphenyls (PCBs) and phenobarbital (50066)(PB) on the induction of liver and kidney tumors by dimethylnitrosamine

(62759) (DMN) were investigated in rats. Male Fischer-344-rats were

maintained on a diet containing 0.04 percent DMN, 500 parts per million (ppm)

PCB, or 500 ppm PB. Rats were divided into 11 groups, each group containing

20 animals. Group 1 was given a DMN containing diet for 2 weeks, a basal diet

for 2 weeks and a PCB diet for 28 weeks. At week 5, animals underwent


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unilateral nephrectomy (UN). Group 2 was given DMN and PCB diets without

UN; group 3 was given PCB plus UN; group 4 was given PCB alone; group 5

was given DMN and PB with UN; group 6 was given DMN and PB; group 7

was given PB plus UN; group 8 was given PB alone; group 9 was given DMN

plus UN; group 10 was given DMN alone; and group 11 was given the basal

diet. All animals were sacrificed at week 32 and complete autopsy was

performed. Rats fed DMN and PCB showed decreased weight gain; the group

given DMN plus PB lost weight during the treatment. In the rats fed DMN and

PCB, with or without UN, the liver was modular with tan nodules. In the

kidneys of rats fed DMN alone, grey nodules were also observed.

Histopathological findings included rounded hyperplastic nodules with

compression of normal liver tissue and constituent hepatocytes were larger than

normal. Hepatocellular carcinoma demonstrated irregular trabecular

arrangement of hepatocytes and was indicated by nuclear hyperchromatin and

increased mitotic index. Cholangiofibrosis demonstrated severe bile duct

proliferation with prominent fibrosis. Adenocarcinomas of kidney were

composed of clear cells arranged in solid, alveolar patterns. The authors

conclude that PCBs and PB promote the production of nodules and

hepatocellular carcinomas in rats pretreated with DMN. (Arai et al, 1983)

Study #9

urothelial cancer [including kidney cancer] relative risks for PCB

exposures were 3.6, after adjusting for year of birth and smoking

A case control study of the association between exposure to benzene (71432),

exhausts, and other industry related chemicals and the risk of urothelial cancer

was conducted. The cohort consisted of 320 cases of urothelial cancer

occurring in males living in Stockholm, Sweden between 15 September 1985

and 30 November 1987 who were born between 1911 and 1945. The referents

consisted of 363 randomly selected residents of Stockholm. The subjects were

interviewed by questionnaire to obtain information on exposures, occupational

history, and smoking and dietary habits. Detailed information was sought on

exposure to benzene, combustion gases from coal, gasoline, and other products,

cutting fluids, asbestos (1332214), aromatic amines, polychlorinated biphenyls(PCBs), and other chlorinated organic compounds. Two cases reported

significant exposure to aromatic amines; they were omitted from further

analysis. The urothelial cancer relative risk (RR) for current and former

smokers was 3.5 and 2.0, respectively. Crude RRs for exposure to benzene and

PCBs were 1.9 and 2.9, respectively. After adjusting for year of birth and

smoking, the RRs for benzene and PCB exposures were 2.0 and 3.6,


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respectively. The risk due to benzene exposure increased with increasing

estimated dose for subjects who had been exposed for at least 20 years before

the study. Cases who had moderate or high annual exposures to gasoline and

diesel exhausts had an RR of 7.1. After controlling for any annual exposure to

benzene the RR was reduced to 5.1. Current smokers exposed to benzene had

an RR of 7.5. Subjects exposed to benzene who also had high dietary intakes of

fried foods and fat had RRs of 9.3 and 10.7, respectively. Subjects exposed to

benzene who were not taking vitamin-A supplements had an RR of 5.8

compared to those taking vitamin-A. When categorized by occupation and

industry, the highest risk was associated with employment in the rubber

industry. The authors conclude that exposure to benzene is associated with an

increased risk of urothelial cancer. The risk depends on mean annual dose and

exposure has to start at least two decades before the observation period.

(Steineck et al, 1990a)

Study #10

for PCBs and urothelial cancers, data are scarce (prior to 1990)

In a previous cohort study by our group, certain industry-related chemicals

were judged as warranting further attention as possible urothelial carcinogens.

In this paper, the epidemiologic literature of cancer of the lower urinary tract is

evaluated for these substances. We would like to add combustion gas/soot from

coal to the substances considered as increasing the risk urothelial cancer. It is,

however, uncertain whether this risk is due to contaminants of aromatic amines

in tar volatiles or whether it depends on other agents, such as nitroarenes or

polycyclic aromatic hydrocarbons. Furthermore, we find some support for the

hypothesis that exposure to chlorinated aliphatic hydrocarbons increases the

risk of urothelial cancer. For creosote, cutting fluids and cutting oils, hair dyes,

and polychlorinated biphenyls, data are scarce. Available data do not support

the hypothesis that asbestos is associated with urothelial cancer. "Publication

bias" such that only limited (Steineck et al, 1990b)

Study #11

one cohort study gave some support for PCBs being associated with

urothelial cancer

The purpose of this thesis was to identify the risk factors for urothelial cancer.

Two cohorts were followed up and a case-referent study was made in the

county of Stockholm in 1985-87. Pipe smoking increased and intake of

supplements (mainly containing vitamin A) decreased the risks. The hypothesis


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that intake of browned material formed during cooking is an important risk

factor was supported in a case-referent study. A dose-response relationship was

also seen with an increasing average daily intake of fat. One cohort study gave

some support for combustion gases from coal, creosote and polychlorinated

biphenyls being associated with urothelial cancer. In the case-referent study,

benzene was identified as a possible risk factor. In the epidemiological

literature, among industry-related chemicals, only certain combustion gases

from coal, besides aromatic amines, have convincingly been linked to urothelial

cancer. (Steineck, 1990c)

Study #12

PCBs increased risk of urothelial cancer

We have previously reported a study in which a job-exposure matrix was

applied to census data, identifying, e.g., polychlorinated biphenyls (PCBs) andcreosote as increasing the risk of urothelial cancer. In this article, we expand on

some theoretical issues, and present detailed accounts of constructed linkages

for PCBs, creosote, and phenols. For agents of interest, one should emphasize

the positive predictive value rather than the sensitivity in the construction of the

matrix. The reverse is true for confounding factors; to avoid residual

confounding after restriction to subjects unexposed for the confounding factors,

one should emphasize sensitivity, possibly compromising the positive

predictive value. This discrepancy between agents of interest and confounding

factors may limit the application of a general matrix for studying several

different diseases. The construction of the matrix is much harder, if sensitivity

rather than positive predictive value is emphasized for an agent. Confounding

from industry-related agents arises due to a true mixed exposure in certain work

tasks, but also due to a gross classification of occupations in the census. One

should not confuse different levels of the positive predictive value with

exposure dose. A "dose-response" with different levels of positive predictive

value reflects an accuracy of the matrix, not a biological phenomenon. Studies

with exposure information from a job-exposure matrix applied to registers with

scant information on occupation and industry may be warranted for exposures

and diseases for which previous studies with a detailed documentation ofexposure have low precision. (Plato et al, 1993)

Study #13

PCBs altered kidneys histopathology

PCB congener 118 accumulated in kidneys


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A study was conducted on the toxic effects of 3,3',4,4'-tetrachlorobiphenyl

(32598133) (PCB-77) and 2,3',4,4',5-pentachlorobiphenyl (32598144) (PCB-

118) following dietary exposure. The effects of PCB-77 and PCB-118 on

various biological parameters were assessed following treatment of Sprague-

Dawley-rats with up to 10,000 parts per billion (ppb) PCB-77 or PCB-118 for

13 weeks. No clinical evidence of toxicity was observed. Increases in the

absolute and relative spleen weights of male rats treated with 1,000 or

10,000ppb PCB-77 were noted. Treatment related biochemical changes

included increases in the activity of hepatic microsomal ethoxyresorufin-O-

deethylase in animals treated with the highest doses of PCB-77 or PCB-118. A

significant decrease in the liver vitamin-A content was seen as well in animals

treated with the highest dose of PCB-77. An increase in the concentration of

3,4-dihydroxyphenylacetic-acid was seen in the brains of males exposed to the

highest dose of PCB-77 while females treated with 2,000ppb PCB-118

exhibited significant decreases in levels of dopamine and homovanillic-acid in

selected areas of the brain. Histopathologic treatment related alterations were

identified in the livers, thyroid glands, spleens, kidneys, and bone marrow of

both PCB-77 and PCB-118 treated animals. A dose dependent accumulation of

PCB-118 was noted in the fat and liver of treated animals with lower levels

identified in the kidneys, brains, and hearts. In contrast, measurable PCB-77

levels were detected only in the fat and liver of the highest dose animals. Based

on these data the no observed adverse effect level for PCB-77 was calculated to

be 100ppb in the diet or 8.7 micrograms/kilogram body weight per day while

that for PCB-118 was 200ppb in the diet or 17 micrograms/kilogram body

weight per day. (Chu et al, 1995)

Study #14

PCBs had physiological effects on kidney function

long-term cancer risks (beyond 8 years) were not followed

In response to a request from the Indiana State Board of Health, a follow up

study was conducted of workers occupationally exposed to polychlorinated-

biphenyls (1336363) (PCBs) at the Westinghouse Electric Corporation's

Transmission and Distribution Components Division (SIC-3629), Bloomington,Indiana. A cross sectional study had been conducted in 1977. Workers in the

high and low serum PCB groups from that study were invited to participate; 60

of 66 workers originally studied participated in this study. Those in the high

level group were on the average 5.6 years older than the low PCB group. Use

of PCBs was discontinued in 1977. By 1985 the levels of serum PCB

concentrations in the low group had decreased by an average of 85% of the


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1977 value. Levels in the high PCB group had decreased by an average of 90%.

No clinical abnormalities attributable to PCB exposure were noted. Serum PCB

levels were positively and significantly correlated with triglycerides,

cholesterol, total bilirubin, conjugated bilirubin, beta-glucuronidase, 5'-

nucleotidase, serum apolipoprotein-Al, serum apolipoprotein-B, urinary

creatinine, and urinary alanine-aminopeptidase. According to the authors, the

biochemical findings are indicative of the physiological effects of PCBs on

lipid metabolism, liver function and kidney function. The clinical significance

of these findings 8 years after occupational exposures had ceased is unknown.

(Steele et al, 1990)

Study #15

PCB-induced enzymes were highest in the kidney and liver

this pattern was in accord with observations in other species

The summer flounder, Paralichthys dentatus, is a commercially important

species of flatfish found on the East Coast of the United States, from Cape

Hatteras to Maine. Pelagic, stomachless larvae metamorphose into the benthic,

gastric, juvenile flatfish in shallow coastal bays, lagoons and estuaries during

the spring. In summer flounder, metamorphosis is regulated by thyroid

hormones (TH), and chemically induced hypothyroidism inhibits

metamorphosis past the very early stages. PCBs are among the major pollutants

found in industrially impacted coastal ecosystems, and are known to act as

endocrine disrupters by lowering blood TH levels in mammals and some fish.

This project is concerned with determining the developmental effects of the

dioxin-like CB 126 on metamorphosing larvae, and ultimately to understand if

any of the effects are mediated by thyroidal disruption. Here we present results

of the first experiments carried out 30-day-old (premetamorphic) and 39-day-

old, (early metamorphosing) larvae to establish their sensitivity to CB 126.

Larvae were exposed to radiolabeled CB 126 through the water, and grown out

for 3 weeks to assess mortality. Cytochrome P4501A1 immunoreactivity was

measured as a marker of Aryl hydrocarbon Receptor pathway activation in

liver, small intestine, stomach, and kidney. Mean metamorphic stage was

calculated at the end of growout to determine if sublethal doses had an effect onmetamorphosis. The younger group appeared more sensitive than the older (LD

20 = 20.9 pg/mg and 170 pg/mg, respectively). Sensitivity to CB 126 was

similar to that observed in embryos of other marine fish (e.g. Fundulus

heteroclitus). CYP1A1 induction was highest in the kidney and liver, lowest in

anterior intestine, and was maximal near the LD 20 in all tissues; this pattern

was in accord with observations in other species. In the younger group we


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observed a dose-dependent trend toward more advanced metamorphic stage,

suggestive of an effect of CB 126 on developmental rate. (Soffientino et al,

2002)

Study #16

PCB mixture Aroclor 1248 caused loss of kidney cell viability and

cell death in a concentration- and time-dependent manner

individual PCB congeners produced kidney cell death by different

mechanisms

The effects of a commercial polychlorinated biphenyl (PCB) mixture (Aroclor

1248) and two individual PCB congeners were evaluated on rat renal proximal

tubule culture cell viability and internucleosomal DNA fragmentation (DNA

ladder) characteristic of apoptosis. Treatment with Aroclor 1248 caused the

loss of cell viability and promoted apoptosis in a concentration- and time-dependent manner. The two PCB congeners assessed can also induce apoptosis.

However, the extent of apoptosis generated was greater for the non-ortho-

substituted planar congener (3,3',4,4-tetrachlorobiphenyl) than for the di-ortho-

substituted nonplanar congener (2,2',4,4',5,5'-hexachlorobiphenyl). This

correlated with the loss of cell viability since the planar compound is much

more cytotoxic. The results suggest a different molecular mechanism in the

induction of apoptosis by planar or nonplanar PCB congeners. (Perez-Reyes, et

al, 2001)

Study #17

PCBs were associated with abnormal cellular changes in the renal

corpuscle (kidneys)

The purpose of this study was to evaluate the potential toxic effects of chronic

sublethal polychlorinated biphenyl (PCB) exposure on feral fish, using

histopathology as an endpoint. Histopathological study of bream (Abramis

brama) and asp (Aspius aspius) living in a PCB-polluted freshwater lake

revealed abnormal cellular changes in the renal corpuscle of both species.

Dilation of glomerular capillaries (DGC), mesangial edema (ME), an adhesionbetween visceral and parietal layers of Bowman's capsule (ABC), and filling of

Bowman's space (FBS), were highly prevalent features in lake fish. The

prevalence of each of these lesions was significantly lower, or totally absent in

fish caught from reference locations. Cellular alterations in liver, gill, gonads,

spleen, and intestine were all linked to seasonal changes. The results suggest

that some of the observed histopathological changes in renal glomeruli,


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particularly DGC and ME, could possibly indicate a prolonged chemical stress

caused by PCBs and related compounds. It is also possible that chronic PCB

exposure may have suppressed and weakened the immuno systems of exposed

fish making them more vulnerable to secondary parasitic infections. (Koponen

et al, 2001)

Study #18

PCBs increased the kidney dysfunctions caused by trichloroethylene

exposure

Several polyhalogenated biphenyls are known to be ubiquitous environmental

contaminants. Male ICR mice were fed a control diet or the same diet

supplemented with 100 ppm polybrominated biphenyl (PBB) or 200 ppm

polychlorinated biphenyl (PCB) for 28 days before single i.p. injections of

various quantities of trichloroethylene (TRI), tetrachloroethylene (TET), 1,1,2-trichloroethane (TCE), or carbon tetrachloride (CCl4). The ratio of liver weight

to body weight was increased by dietary PBB and dietary PCB. PBB appeared

to be more potent in this respect. Functional damage to the liver (elevated

serum glutamic oxaloacetic transaminase activity) was not produced by acute

administration of TRI, TET or TCE. CCl4-induced liver damage was greater in

PCB-treated mice than in controls, and greater in PBB-treated than in PCB-

treated mice. Functional renal damage (elevated blood urea nitrogen

concentration, decreased organic anion transport capacity) was produced by

acute administration of all solvents except TET. TRI-induced renal dysfunction

was potentiated by dietary PBB and dietary PCB. Both TCE-induced and CCl4-

induced renal dysfunction were potentiated by dietary PBB but not by PCB.

Mice fed a diet containing 0, 20 or 100 ppm PBB for 20 days were

subsequently injected with various doses of CCl4 and 96 h LD50 values were

determined. The LD50 CCl4 was lower in mice treated with 20 ppm PBB than

in control mice and lower in mice treated with 100 ppm PBB than in those

treated with 20 ppm PBB. (Kluwe et al, 1979)

Study #19

low amounts of PCBs were enough to modify kidney cell membrane

fluidity

The influence of different polychlorinated biphenyls (PCBs) upon dynamic

properties of membranes from rat renal tubular cell cultures has been

investigated. Studies have been realized with Aroclor 1248 (a commercial PCB

mixture with 48% chlorine by weight), and two pure PCB congeners: 3,3',4,4'-


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tetrachlorobyphenyl (a coplanar compound) and 2,2',4,4',5,5'-

hexachlorobiphenyl (an ortho-substituted nonplanar congener). Changes in the

membrane fluidity were measured by the fluorescence polarization technique

using the probe diphenylhexatriene. The treatment of cells with Aroclor 1248

increased membrane fluidity in a dose-dependent manner. Even though rat

renal tubular cell cultures accumulated only a low amount of PCBs when cells

were incubated in presence of the toxicant, that small quantity was enough to

modify the membrane fluidity. Interestingly, a significant increase of

membrane fluidity was found in presence of 2,2',4,4',5,5'-hexachlorobiphenyl,

but no significant dif [incomplete abstract] (Lopez-Aparicio, et al, 1997)

Study #20

kidney damage is one of the main PCB effects in birds

The current knowledge about polychlorinated biphenyls (PCBs) including thetoxicology of these compounds as well as the levels of PCBs found in nature is

summarized and evaluated. A number of studies including acute single dose,

acute feeding and sublethal dose experiments are cited. A fair amount of

information has been collected about PCBs but the toxicology of these

compounds is poorly known in comparison to that of chlorinated pesticides. No

definite work has been done to establish LD50 values for the various

formulations of PCBs. The most important effects of the PCBs are their long-

range sublethal effects. The most common ones in the rat, guinea pig and rabbit

as well as in the chicken and Bengalese finch are summarized. PCBs mainly

cause pathological changes in the liver of guinea pigs, rats and rabbits. The

changes include moderate atrophy, necrosis and weight increase. The main

effect of PCBs in birds are increased fluid in the pericardial sac, renal damage

and reduction in size and/or atrophy of the spleen. PCB residues have been

found in wild life from Great Britain, Sweden, Canada, Germany, the

Netherlands and from the United States. Like DDT, PCBs are capable of

accumulating as they advance up the food chain. Recent studies by Risebrough

et al. (1968 and 1970) show that twice as much PCB as DDT has been found in

the tissues of some seabirds in San Francisco Bay. Evaluation of the available

data on PCBs in tissues tends to parallel that of DDE, at least in industrialareas. The DDE rate is lowest near industrial areas, indicating that PCBs are

not carried quite as readily to remote areas. More research is needed to

ascertain the presence of PCBs in higher forms of life and the effects of this

presence. Finding the major source(s) of PCBs entering the environment is the

most critical area for research. Once the leak is found, strong legislative control

should be enacted to stop it.


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Study #21

kidney enzyme activities were increased by PCBs

kidney toxicity of chloroform was reduced by PCBs

ICR mice were treated with phenobarbital (PB), 3-methylcholanthrene (3MC),TCDD or PCB. Renal and hepatic microsomal enzyme activities were

increased by 3MC, TCDD and PCB. Hepatic, but not renal, microsomal

enzyme activities were increased by PB. Toxicity of chloroform to the liver

was increased by PB pretretment. Pretreatment with TCDD, however,

decreased hepatotoxicity of chloroform. No effect of chloroform toxicity to the

liver was noted by pretreatment with 3MC or PCB's. Renal toxicity of

chloroform was reduced by TCDD or PCB pretreatment, but no effect by PB

was noted on kidney damage caused by chloroform. These results suggest that

the chloroform metabolites ultimately responsible for renal and liver damage

are not generated at a common site. The metabolite probably responsible forliver damage is apparently generated in the liver, and similarly, the one

responsible for kidney damage, in the kidney.

Study #22

certain PCBs decreased liver Vitamin-A content 60% within 7 days,

and increased kidney Vitamin-A levels 3-fold

The kinetics of liver and kidney retinol and retinyl-palmitate levels were

examined following single intraperitoneal injections of DDT (50293), 2,2',5,5'-tetrachlorobiphenyl, 3,3',4,4'-tetrachlorobiphenyl (32598133), or 2,2',4,4',5,5'-

hexachlorobiphenyl (35065271) to male Sprague-Dawley rats. The

polychlorinated biphenyls (PCBs) were given in doses of 300

micromoles/kilogram (micromol/kg), and DDT was a given at a dose of

150micromol/kg. Administration of 3,3',4,4'-tetrachlorobiphenyl, but not the

other PCBs, decreased total liver vitamin-A content within 7 days of

administration. This decrease left vitamin-A levels of 40 percent of control

animals. A three fold rise in kidney vitamin-A, primarily retinol, accompanied

he decrease in liver vitamin-A. Even so, the rise in kidney vitamin-A was

minimal compared to its loss from the liver. The induction of various drug

metabolizing enzymes or retinyl-palmitate-hydrolase activity, a key enzyme in

hepatic retinyl-palmitate hydrolysis, was not implicated in the depletion of

hepatic vitamin-A. It is suggested that chemical or redox changes in the liver as

a result of the toxicity of the xenobiotic may result in the nonenzymatic

destruction of the liver vitamin-A stores.


15/19

Study #23

certain PCBs caused significant increases in kidney retinol (Vitamin-

A) content

Changes in vitamin-A parameters were compared with the kinetics of inductionof various drug metabolizing enzyme activities using 1,1,1-trichloro-2,2-bis-(4-

chlorophenyl)ethane (50293) (DDT) and several prototypic polychlorinated

biphenyls (PCBs). Weanling male Sprague-Dawley-rats were given a single

intraperitoneal injection of a synthetic PCB at 300 micromoles/kilogram

(micromol/kg) or DDT at 150micromol/kg. Rats were sacrificed 1, 3, 5, or 7

days thereafter. PCBs used included 2,2',5,5'-tetrachlorobiphenyl (2,5-PCB),

3,3',4,4'-tetrachlorobiphenyl (32598133) (3,4-PCB), or 2,2',4,4',5,5'-

hexachlorobiphenyl (35065271) (2,4,5-PCB). Only rats treated with 3,4-PCB

showed a significant decrease in whole liver vitamin-A content during the first

week following treatment. A significant increase was noted in kidney retinolcontent. Only 2,5-PCB and 3,4-PCB altered serum retinol levels, with

decreases on days 1, 3, and 5 following treatment. DDT and 2,4,5-PCB

increased cytochrome-P-450 content and the activities of aminopyrine-N-

demethylase and aldrin-epoxidase in liver. No change was noted in any

vitamin-A parameter in DDT or 2,4,5-PCB exposed livers. Only marginal

changes in drug metabolizing enzyme activities were induced by 2,5-PCB. 3,4-

PCB was a potent inducer of cytochrome--P-450 dependent benzo(a)pyrene-

hydroxylase, aryl-hydrocarbon-hydroxylase, and uridine-diphosphate-

glucuronosyltransferase activity. Treatment with 3,4-PCB also decreased liver

total vitamin-A content and levels of serum retinol and caused a significant

increase in kidney retinol. No highly significant correlations were found among

the vitamin-A levels and drug metabolizing enzyme activities in the liver.

(Azais et al, 1987)

Study #24

sulfur-containing PCB metabolites accumulate in the kidney

Studies of the tissue distribution of polychlorinated biphenyls (1336363)

(PCBs) in laboratory animals were summarized. Twenty eight PCBs and six

chlorinated compounds which are not PCBs were investigated. Studies of the

distribution of carbon-14 labeled PCBs in mice were discussed. Dose and

structure dependent accumulation and long term retention of the compounds in

the tracheobronchial mucosa have been observed. The greatest accumulation

occurred in PCBs having chlorines in the 2,2',4,4',5,5' positions. Most of the

PCBs were present as 4-methylsulfonyl metabolites. Radiolabeling studies have


16/19

indicated that the 4-methylsulfonyl PCB (MeSOPCB) metabolites are bound

initially to a specific MeSOPCB binding protein in the Clara and goblet cells.

This proteineSOPCB complex has been shown to be subsequently secreted into

the airway lumen and spread over the entire surface lining. Studies on the

accumulation of MeSOPCBs in kidney proximal tubular cells in mice were

discussed. These have shown that the extent of accumulation is different from

that of the lung, and apparently depends on the nature of the substituent in the

para position. Accumulation of PCB metabolites in sites outside the lung and

kidney were discussed. MeSOPCBs have been found in the uterine and fetal

soft tissues of mice, the ventral prostate and large intestinal epithelium of rats,

and the cerebral gray matter of quail. Tissue binding of sulfur containing PCBs

which are not xenobiotics was considered. Studies with dimethylsulphone

(67710) and chlorinated benzenes in mice have shown that sulfur containing

metabolites accumulate in the lung, kidney, liver and adrenal cortex. (Brandt et

al, 1987)

Study #25

PCBs increase the protein synthesizing activity of kidney pH 5

supernatant fractions

Homogenates of liver and of kidney cortex were obtained from control rats and

from rats treated with the polychlorinated biphenyls (PCBs) Aroclor 1254, and

were separated into ribosomes and into the postmicrosomal supernatant

fraction. The latter fraction from liver and kidney was used to prepare the pH 5

supernatant fraction, containing elongation factors 1 and 2 (EF 1 and EF 2) for

protein biosynthesis. These fractions were incubated with KCl-washed

ribosomes obtained from control rat liver. The incorporation of

(14C)phenylalanyl-tRNA into peptide was increased with the liver and kidney

preparations derived from the treated rats. The elongation factor 1-dependent

binding of (14C)phenylalanyl-tRNA to ribosomes was also markedly increased

both with the liver and the kidney preparations obtained from the rats that had

received PCBs. (Cappon et al, 1976)

Study #26

kidneys are more sensitive than lungs to PCB enzyme induction

In this report, we have investigated the effect of dietary exposure to Aroclor

1254 (1-100 ppm) given chronically or discontinuously over an 84-day time

interval to the female F344 rat. Cytochrome P4501A was quantified in lung and

kidney by measuring the dealkylation of ethoxyresorufin substrate and by


17/19

Western immunoblotting. P4501A displayed a dose- and time-dependent

increase in both extrahepatic organs. The kidney appeared to be more

responsive to induction than lung at all doses (maximum of 500-fold induction

following 84 days exposure to 100 ppm). Further, there was evidence by

enzymatic activity, immunoblotting and Northern analysis of total RNA for the

presence of 1A2 in the most highly induced kidneys. The decline in 1A

induction observed following discontinuous exposure was more prominent in

the kidney than in the lung. These data demonstrate the sensitivity of kidney to

P4501A induction capacity as compared to lung, although the persistence of the

induction re [incomplete abstract) (Beebe, et al, 1995)

Study #27

PCB mixture Aroclor 1254 altered liver and lung tissue more than

kidney tissue

The effects of a tumor promoting polychlorinated biphenyl mixture, Aroclor

1254, on I-compounds (tissue, species and sex dependent DNA modifications

that increase with age in untreated rodents) were studied by 32P-postlabeling in

male Sprague-Dawley rat liver, kidney, and lung DNA. Aroclor 1254 was

dissolved in corn oil and intraperitoneally (i.p.) injected (2 X 500 mg/kg, 2

weeks apart) into 3-month-old rats. Control rats were given corn oil. Groups of

3 animals were sacrificed at 2 and 6 weeks after the second injection of corn oil

or Aroclor 1254. At both time points Aroclor 1254-treated rats had significantly

lower body weights and higher liver weights while kidney and lung weights

were unaffected. Thymidine incorporation into liver and lung DNA was

significantly increased at both time points, while kidney DNA showed a small

decrease at 2 weeks. Treatment resulted in significant reductions (ranging from

29 to 100%) of each of nine liver I-spots at 2 and 6 weeks. In treated rats there

was no decrease in kidney I-spots at 2 weeks, while the levels of only two out

of ten kidney spots were reduced by 42-91% at 6 weeks. At 2 weeks three out

of seven and at 6 weeks four out of seven lung I-spots were lowered by 51-

100% in the Aroclor 1254-treated rats. Thus the effects decreased in the order

liver > lung > kidney. Since Aroclor 1254 has been reported to be a tumor

promoter in liver and lung but not kidney, these results suggest a correlationbetween organ specific promotion of carcinogenesis by Aroclor 1254 and the

reduction of DNA I-compounds. (Nath et al, 1991)

Study #28

PCBs promoted liver cancers, but not kidney cancers, in rats treated

with nitrosamines


18/19

The effects of phenobarbital (PB), polychlorinated biphenyl (PCB) and sodium

saccharin (SS) on hepatic and renal carcinogenesis induced by N-ethyl-N-

hydroxyethylnitrosamine (EHEN) were examined in male F344 rats. The rats

were given 0.1% EHEN in their drinking water for 2 weeks and then diet

containing 0.05% PB, 0.05% PCB or 5% SS for 32 weeks. In week 3, the right

kidney was removed to promote renal neoplasia. The incidence of

hepatocellular carcinoma was much higher in rats given PB or PCB than in

controls given EHEN alone. PB administration significantly decreased the

average number of renal-cell tumors per unit area and SS reduced the numbers

of early neoplastic nodules. Treatment with PCB had no effect on renal

carcinogenesis. These results indicate that chemicals may have either a

promotive or inhibitory effect depending on the organ. (Hirose et al, 1981)

Study #29

incomplete abstract --- study may correlate PCBs and kidney cancer

The validity of retrospective assessment of occupational exposure greatly

depends on the amount of detail in the available information, on the knowledge

of the specific industrial process by the experts, and on the criteria adopted to

define relevant exposure. These criteria are difficult to standardize and are

rarely made explicit in published reports, which makes it difficult to interpret

inconsistencies among different studies. In two ongoing case-control studies on

kidney cancer and, respectively, malignant lymphomas, a detailed occupational

history was obtained and supplemented by 19 additional questionnaires,

specifically addressing industrial activities where the knowledge of job title

alone would have been insufficient for reliable exposure assessment. One

further questionnaire was used to collect details of task and environment for all

the other activities. These data are used to establish probability, intensity and

frequency of exposure to 30 substances known [incomplete abstract] (Belletti

et al, 1993)

Upcoming Research

SINCLAIR JA. EFFECTS OF ARSENIC ON CYTOCHROME P450 Source:Crisp Data Base National Institutes of Health. Author Address:

DARTMOUTH MEDICAL SCHOOL, HANOVER, NH 03755-3835

arsenic modulates the accumulation and elimination of PCBs

arsenic is associated with kidney cancer


19/19

PCB accumulation may boost arsenics tendency to produce kidney

cancer

[Northeast Wisconsin has many areas of high arsenic levels in

drinking water]

Arsenic is found at high levels in almost half of all Superfund sites as well asmany public and private water supplies in the northeastern and western regions

of the United States. High levels of arsenic in drinking water are associated

with an increased risk of skin, bladder, lung, and kidney cancer. Previous work

in this and other laboratories has demonstrated that arsenic can have substantial

effects on specific cytochrome P450s (CYPs) that are principally responsible

for metabolism of drugs and other xenobiotics by the liver, lung and other

organs. In particular, arsenic exposure decreases the induction of CYPs by

chemicals that are subsequently metabolized by these CYPs. We hypothesize

that arsenic-induced alterations in CYP mediated xenobiotic metabolism may

have a significant impact on the response of humans and other organisms to

other toxic chemicals, which might occur in Superfund sites containing arsenic

in combination with other metals and organic contaminants. This is postulated

to increase the bioaccumulation of other toxic chemicals, and therefore these

effects may contribute to arsenic- induced cancer and vascular disease and/or

enhance the toxicity of other chemicals. The overall goal of this project is to

determine the effects of arsenic (II I) and other selected metals on specific liver

CYPs. Our previous studies have demonstrated in hepatocytes in culture that

low concentrations of arsenic significantly decrease induction of several major

CYPs. These arsenic mediated decreases are not due to the induction of hemeoxygenase, depletion of heme, or oxidative damage as had been previously

postulated. We hypothesize that these effects occur mainly at the post-

transcriptional level. Our specific aims will be to: 1) determine in intact rodents

the effects of acute and chronic exposure to arsenic (III) on induction of CYPs,

and the ability of arsenic to modulate accumulation and elimination of

polychlorinated biphenyls and drugs; and 2) determine, in cultured hepatocytes,

the post-transcriptional mechanisms by which arsenite specifically decreases

synthesis of rat CYPA23 and chick CYP2H1. These studies may provide

insight into effects of arsenic and other toxic metals, in combination with

exposures to other toxic agents, that have not previously been appreciated.Since most Superfund sites and other waste sites contain complex mixtures of

toxins, and over 60% of these sites contain toxic metals, understanding their

effects when present in combinations will be important for our overall

evaluation of the health effects of these agents.

studies of kidney cancer and pcbs

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