dietary exposure to furocoumarins

REGULATORY TOXICOLOGY AND PHARMACOLOGY 14,26 l-272 ( 199 1)

Dietary Exposure to Furocoumarins

D. JESSE WAGSTAFF

Center for Food Safety and Applied Nutrition, Food and Drug Administration, Washington, D.C. 20204

Received January 8, 1991

Natural furocoumarins, some of which are carcinogenic, are widespread components of the diet which are Frequently consumed. Because of the paucity of samples, the wide scatter of analytical values, and other limitations in the data, only broad conclusions can be drawn. Most of the exposure is from limes, with smaller amounts coming from other citrus and umbelliferous food plants. The per capita exposure is estimated to be 1.3 mg per day. Exposure can be reduced through controlling stress in growing plants and stored food products. Because furocoumarins are one class of a large group of chemicals in a defensive system essential to plant survival, their total eradication is not possible. Further research is needed to assess their health risk. o 1991

Academic Press, Inc.

INTRODUCTION

Food safety involves both synthetic and natural toxic substances. The U.S. Food and Drug Administration has established a database of natural carcinogens in foods which includes information on literature citations for carcinogenesis in animals and humans; identity of chemical compounds; plant, animal, and mineral sources of carcinogens; their concentrations in these food sources and in prepared food dishes; and food intake data. Natural anticarcinogens and other factors which may affect food safety are also being included. This information is used to support exposure and risk assessments upon which regulatory decisions are based.

Until recently, the main natural toxicants of concern have been aflatoxins. These compounds are related to coumarin, form adducts with DNA, and are potent animal carcinogens. However, their carcinogenic potency in humans is uncertain (WagstaE, 1985). Furocoumarins were selected as the pilot class of chemicals for database de- velopment because they also are derived from coumarin, form adducts with DNA, and, after activation by ultraviolet light, cause cancer in animals and humans (Cart- wright and Walter, 1983; Dunnick, 1989; Stem, 1990). In addition, furocoumarins can exert phototoxicity by mechanisms other than those involving DNA, such as free radical production (Black et al., 1989). Furthermore, furocoumarins are widely used in medicine, primarily in treating psoriasis and other skin disorders (Stem, 1990).

261

0273-2300/91 $3.00 Copyright 0 1991 by Academic Press, Inc. All fights of reproduction in any form nsrved.

262 D. JESSE WAGSTAFF

They are found in a wide variety of plants in all climatic zones and occur at higher concentrations than aflatoxins (Beier, 1990).

Furocoumarins are produced by certain types of plants to aid in defense against invaders and predators including viruses, bacteria, fungi, insects, and animals. They have been called natural pesticides or phytoalexins (Beier and Oertli, 1983) and gen- erally occur in a defensive line in the skin of the plant.

The furocoumarins evaluated here are psoralen, angelicin, and other naturally occurring compounds containing these two fused ring structures. Potencies for acute and chronic toxicity vary among the different chemicals of the class, and a large number of similar compounds are phototoxic or DNA-reactive, but these considerations are beyond the scope of this presentation. The aim of this paper is to estimate total dietary exposure to furocoumarins.

METHODS

Furocoumarin Compounds

The natural furocoumarins in major U.S. food plants are listed in Table 1 (Gray and Waterman, 1978; Pathak et al., 1962; Stanley and Jurd, 197 1). Major food plants are those reported eaten in the USDA food intake survey described below. Natural furocoumarins in minor food plants are given in Table 2. A common name for each

TABLE 1

FUROCOUMARINS WHICH GCCUR IN MAJOR FOODS

Common name CAS No. Side chains on the furocoumarin fused ring

Angelicin derivatives Angelicin Sphondin

Psoralen derivatives - - - - -

Bergamottin Bergapten Bergaptol Byakangelicin Imperatorin Isoimperatorin Iaopimpinellin Oxypeucedanin Oxypeucedanin

hydrate Phellopterin Psoralen Xanthotoxin

523-50-2 None 483-66-9 6-Methoxy-

69239-53-8 71612-25-4 7 1339-34-9

- -

7380-40-7 484-20-8 486-60-2 482-25-7 482-44-O 482-45-l 482-27-9

2609 l-73-6

2643-85-8 4-(2,3-Dihydroxy-3-methylbutoxy)-, (R)- 2543-94-4 4-Methoxy-9-[(3-methyl-2-butenyl)oxy]-

66-97-7 None 298-8 1-7 9-Methoxy-

4-[(3,7-Dimethyl-2,6-octadienyl)oxy]-9-methoxy-, (E)- 9-[(3,7-Dimethyl-2,6octadienyl)oxy]- 4-[(6,7-Dihydroxy-3,7dimethyl-2-octenyl)oxy]- 4-[(3,6-Dimethyl-6-formyl-2-heptenyl)oxy]- 4-[(3,7-Dimethyl-6-epoxy-2-octenyl)oxy]- 4-[(3,7-Dimethyl-2,6octadienyl)oxy]-, (E)- 4-Methoxy- 4-Hydroxy- 9-(2,3-Dihydroxy-3-methylbutoxy)&methoxy-, (R)- 9-[(3-Methyl-2-butenyl)oxy]- 4-[(3-Methyl-2-butenyl)oxy]- 4,9Dimethoxy- 4-[(3,3-Dimethyloxiranyl)methoxy]-, (S)-

Common name

DIETARY EXPOSURE TO FURGCOUMARINS 263

TABLE 2

FURCCOIJMARINSWHICHOELJRINMINOR FOODS

CAS No. Side chains on the furocoumarin fused ring

Angelicin derivatives Columbianetin lsobergapten Oroselone Pimpinellin

Psoralen derivatives - -

Alloimperatorin Benahorin Byakangelicol Chalepensin Furopinnarin Heraclenin Heraclenol Isooxypeucedanin Pangelin Peucedanin Rutolide Tederin Xanthotoxol

Dihydropsoralen derivatives

-

3804-70-4 8,9-Dihydro-8-( I-hydroxy-I-methylethyl)-, (S)- 482-48-4 5-Methoxy-

1760-27-6 8-( I-Methylethenyl)- 131-12-4 5,6-Dimethoxy-

105866-29-3 5-[(6,7-Dihydroxy-3,7dimethyl-2-octenyl)oxy]- 1603-47-o 9-Hydroxy-4-methoxy- 642-05-7 9-Hydroxy-4-(3-methyl-2-butenyl)-

34155-80-I 4-( I, 1 -Dimethyl-2-propenyl)-9-methoxy- 26091-79-2 9-[(3,3-Dimethyloxiranyl)methoxy]-4-methoxy-, (R)- 13164-03-9 6-( 1, I-Dimethyl-2-propenyl)- 23531-95-5 9-( 1, I-Dimethyl-2-propenyl)-4-methoxy- 2880-49- 1 9-[(3,3Dimethyloxiranyl)methoxy]-, (R>

3 1575-93-6 9-(2,3-Dihydroxy-3-methylbutoxy)- 5058-15-l 4-(3-Methyl-2-oxobutoxy)-

33783-80-l 4-[(2-Hydroxy-3-methyl-3-butenyl)oxy]-, (R)- 133-26-6 3-Methoxy-2-( I-methylethyl)-

50886-70-9 6-(2,2-Dimethylcyclopropyl)- 39262-34-5 9-Methoxy-4-( 1 -methylethoxy)- 2009-24-7 9-Hydroxy-

Chalepin

Isorutarin

Marmesinin

Nodakenetin Nodakenin

Rutamarin

Rutarin

Rutaretin

Xanthoamol Other furocoumarins

Athamantin

121498-42-g

13 164-04-o

53846-51-g

495-30-7

495-32-9 495-31-8

14882-94-1

20320-g 1-4

13895-92-6

5 1580-96-2

1892-56-4

Ostruthol 642-08-o

2,3-Dihydro-2-( I-hydroxy-I-methylethyl)-9- methoxy-

6-( I,1 -Dimethyl-2-propenyl)-2,3-dihydro-2-( l- hydroxy-I-methylethyl)-

2-[ I-(/3-D-Glucopyranosyloxy)- 1 -methylethyl]-2,3- dihydro-9-hydroxy-, (R)-

2-[ I-(@&lucopyranosyloxy>l-methylethyl]-2,3- dihydro-, (S)-

2,3-Dihydro-2-( I-hydroxy-I-methylethyl)-, (R)- 2-[ I-(&BGlucopyranosyloxy)-I-methylethyl]-2,3-

dihydro-, (R)- 2-[ I-(Acetyloxy)- I-methylethyl]-6-( 1, I-dimethyl-2-

property])-2,3-dihydro- 9-(b-D-Glucopyranosyloxy)-2,3dihydro-2-( l-

hydroxy- 1 -methylethyl)- 2,3-Dihydro-9-hydroxy-2-( l-hydroxy-l-

methylethyl)-, (S)- 2,3-Dihydro-3-hydroxy-2-( I-hydroxy-1-methylethyl)

3-Methylbutanoic acid 8,9dihydro-8-[ 1 -metbyl-I- (3-methyl-1-oxobutoxyjethyfl-2-oxo-2Kfuro[2,3- h]- 1 benzopyran-9-yl ester, (8 S-c@

2-Methyl-2-butenoic acid 2-hydroxy-2-methyl-l- [[(7-0x0-7H-furo[3,2-g][ I]benzopyran-4-yl)oxy]- methyllpropyl ester, (R-(Z))-

264 D. JESSE WAGSTAF’F

chemical is given if known. Synonyms for these common names are not listed here but are available in Chemical Abstracts (Chemical Abstracts Service, 1985). The Chemical Abstracts Service Registry Number (CAS) is given for each chemical. The ring carbon numbering system and the naming of the side chains follows the rules used in the Ninth Collective Index of Chemical Abstracts (9CI) (Chemical Abstracts Service, 1985). The main group of furocoumarins is composed of the linear furocoumarins; they are derived from psoralen in which the three rings are in a line. The 9CI name is 7H-furo[3,2-g][ llbenzopyran-7-one and its structure is given below.

However, in the most common naming scheme the number 9 ring carbon in the 9CI scheme is numbered 8 and carbon 4 is numbered 5. For example, one of the common linear furocoumarins, bergapten, bears the 9CI name, in the inverted format, of 7H-furo[3,2-g][ llbenzopyran-7-one, 4-methoxy, but it is usually called 5-methoxy- psoralen, or 5-MOP. In some linear furocoumarins the double bonding at carbons 2 and 3 of the furan ring is saturated and they are named dihydrofurocoumarins. Still other linear furocoumarins have a large side chain on carbon 2 of the furan ring and are named as derivatives of that side chain rather than as psoralen derivatives.

Furocoumarins in the second group are called angular furocoumarins because the furan ring is attached at an angle to the coumarin ring. The unsubstituted ring is called angelicin, its 9CI name is 2H-furo[2,3-h]-l-benzopyran-2-one, and its structure is given below.

FOOD PLANTS

Table 3 is a list of the major food plants which contain furocoumarins. Table 4 is a list of plant genera of minor food plants which contain furocoumarin. Some citrus fruits are major components of the diet; others such as kumquat, tangerine, and man- darin orange are eaten less frequently and are classified in this report as minor foods. Botanical names are those listed by Mabberley (1989). Figs contain furocoumarin in their leaves, but despite reports of phototoxicity from eating the fruit, no furocoumarin has yet been found in the fruit (Ippen, 1982). Nonfood plants which contain furocou- matins are not listed here but in a checklist of botanical names, common names, and

DIETARY EXPOSURE TO FUROCOUMARINS 265

TABLE 3

MAJOR FOOD PLANTS WHICH CONTAIN FUROCOUMARINS

Plant family Common name Botanical name

Moraceae Rutaceae

Umbelliferae

Fig Grapefruit Lemon Lime Orange Anise Caraway Carrot Celeriac Celery Coriander Dill Parsley Parsnip

Ficus carica L. Citrus X paradisi Macfad. Citrus limon (L.) Bum. f. Citrus aurantiifolia (Christm.) Swingle Citrus sinensis (L.) Osbeck PimpineUa anisum L. Carum carvi L. Daucus carota sativus subsp. (L.) Schuebler and Martens Apium graveolens rapaceum var. (Miller) Gaudich. Apium graveolens duke var. L.; (Miller) Pers. Coriandwm sativum L. Anethum graveolens L. Petroselinum crispum (Miller) Nyman ex A. W. Hill Pastinaca sativa L.

synonyms for carcinogenic and poisonous plants, including those of Tables 3 and 4, which has been submitted elsewhere for publication (Wagstaff, 1990).

CONCENTRATIONS OF FUROCOUMARINS IN FOOD PLANTS

Concentrations of furocoumarins in major food plants are presented in Table 5. Because no national statistically representative samples of food plants have been an- alyzed for furocoumarins, it was necessary to develop criteria for selecting data to be used in evaluation. Published analytical values vary over a range of several-hundred- fold for the same species of plant. Data were excluded for plants which are not typical of marketed produce such as immature, diseased, or rotting plants or plant products. Also data were excluded for plants associated with photodermatitis outbreaks. Many of the plants included in the evaluation were collected in grocery stores near the analytical laboratories. Others were shipped from distant producing areas; and a few plants were grown by the analysts. Only data for fresh, uncooked, healthy plants were used. If mean values for multiple test samples met these criteria, the highest mean was used. Concentrations are on a fresh-weight basis. Analytical values for some edible plant parts could not be found and were extrapolated from data available for other plant parts.

FOOD INTAKE

A national survey of foods eaten by individuals was taken in 1987 and 1988 by the U.S. Department of Agriculture (USDA) (Peterkin et al., 1988). The survey covered a 3day period. The interviewed person, usually the homemaker, was asked to recall the identity and quantity of each food dish and beverage ingested by each household member in the prior 24 hours and was asked to keep a diary of the same information


TABLE 4

MINOR Foot PLANTS WHICH CONTAIN FUR~COIJMARINS

Plant family Genus

Leguminosae

Rutaceae

Caragana Coronilla Aegle Afraegle Atalantia Casimiroa

Umbelliferae

Clausena Limonia Poncirus Ptelea Ruta Triphasia Zanthoxylum Angelica

Cymopterus Heracleum Foeniculum Levisticum Ligusticum Peucedanum Sum Trachyspermum

for the next 2 days. Age, race, sex, and other demographic information were recorded. The data were edited and copied onto computer tape files, which were used in this analysis. There were lo,34 1 respondents in the survey, but in this analysis the records for the 31 persons over 90 years of age were excluded.

A file of ingredients contained in each food, i.e., the recipe, was created by USDA. The items in the ingredients file were matched against the list of major furocoumarin- containing food plants of Table 3. Powders and alcoholic beverages were not included. Also excluded were the ingredients of natural flavorings used in small quantities, which are not identified on food labels and are not listed in the food ingredient file.

The food intake file was searched for codes of furocoumarin-containing foods. The total quantity of each matched food eaten by the surveyed person over the 3 days of the survey was calculated. The total amount of each food was first multiplied by the proportion of each furocoumarin-containing plant product in that food dish and then was multiplied by the concentration of furocoumarin in each plant. Finally, the amounts of fi,uocoumarin in all foods eaten by an individual were summed and divided by 3 days to calculate the total milligrams of furocoumarin intake per person per day.

Although some natural products are treated to reduce their furocoumarin content, the food intake data are not adequate to distinguish treated and untreated foods, and therefore all food products and flavors are assumed to be natural and untreated. Citrus fruits, juices, and foods with citrus flavor were assumed to contain 0.25% of citrus oil. No values were found for orange oil. The level of 0.5 ppm used in the evaluation is

Plant


TABLE 5

CONCENTRATION OF FUR~COUMARINS IN MAJOR Foot PLANTS

Part Furocoumarins Concn. (ppm) Reference

Grapefruit Lemon Lime

Oil Oil Oil

Orange Oil Anise Fruit

Caraway Fruit

Carrot Root

Celeriac Fruit

Celery Stalk

Coriander Fruit

Dill Fruit

Parsley Fruit

Parsnip Root

Bergapten 120 Bergapten 33 Bergamottin 30,250 CAS 69239-53-8 9,450 CAS 71612-25-4 1,050 Imperatorin 180 Isoimperatorin 330 Isopimpinellin 5,080 Phellopterin 110 Oxypeucedanin hydrate 250 Total in lime oil 46,700 Bergaptol 0.5 Bergapten 0.005 Xanthotoxin 0.005 Total in anise fruit 0.01 Bergapten 0.005 Xanthotoxin 0.005 Total in caraway fruit 0.01 Bergapten 0.01 Xanthotoxin 0.01 Total in carrot root 0.02 Bergapten 16.9 Isopimpinellin 0.1 Total in celeriac fruit 17 Bergapten 0.6 Psoralen 1.0 Xanthotoxin 7.2 Total in celery stalk 8.2 Bergapten 0.005 Xanthotoxin 0.005 Total in coriander fruit 0.01 Bergapten 0.005 Xanthotoxin 0.005 Total in dill fruit 0.01 Bergapten 12.4 Imperatorin 1.4 Isoimperatorin 5.6 Oxypeucedanin 25.7 Psoralen 1.4 Xanthotoxin 0.1 Total in parsley fruit 47 Angelicin 34 Bergapten 7 Psoralen 7 Xanthotoxin 48 Total in parsnip root 96

Shu et al. (1975) Shu et al. (1975) Stanley and Vannier ( 1967)

Fisher and Trama ( 1979) Ceska et al. ( 1987)

Ceska et al. ( 1987)

Ceska et al. (1986a)


Beier et al. ( 1983)

Ceska et al. (1987)

Ceska et al. (1987)


Ceska et al. ( 1986b)


based on the report of Fisher and Trama (1979) on bergaptol in orange oil and assumes a detection limit of 0.5 ppm.

RESULTS AND DISCUSSION

The major dietary source of furocoumarins is limes, as seen in Table 6. Part of this value is due to lemon-lime flavored carbonated beverages. Even if these drinks were not considered in the calculation, the majority, i.e., 70% of the exposure would still be attributable to limes. These extraordinarily high concentrations for limes are in accord with reports of clinical photodermatitis in humans (Gross et al., 1987). Lesions in some cases were so severe that they mimicked lesions of child abuse (Coffinan et al., 1985). Lime oil caused phototoxicity when tested in animals and humans (Op dyke, 1974).

The second most important source is celery. Grapefruit, parsley, and parsnip con- tribute only modestly to the total diet load even though there are reports of phototoxicity from exposure to some of these plants (Zaynoun et al., 1985). Carrots, lemons, and oranges make a small contribution. The presence of furocoumarin in oranges is sup- ported by reports of phototoxic cheilitis in people eating oranges (Volden et al., 1983). Anise, caraway, celeriac, coriander, and dill have a neglibible effect.

Citrus fruits are in the Rutaceae plant family, and the other significant sources are from the Umbelliferae family. Furocoumarins probably occur in almost all species of these families. Carrots were thought to contain no furocoumarins and to lack bio- chemical pathways for their production (Ivie et al., 1982). Since then, expanded sampling and use of more sensitive detection methods have shown that even healthy fresh carrots contain furocoumarins in all parts of the plant at very low levels (Ceska et al., 1986a). Fungal infection stimulated a 155-fold increase in furocoumarin production by carrots (Ceska et al., 1986a). Stadler and Buser (1984) have even postulated that the carrot fly detects furocoumarins and related chemicals in carrot leaf wax as a means to identify suitable plants on which to lay its eggs.

The estimate of dietary furocoumarin intake is 1.31 mg per person per day for people eating furocoumarin-containing foods (see Table 7). Eighty percent of the people

TABLE 6

DIETARYFUROCOUMARINCONTRIBUTEDBYEACHFOOD

Total exposure

Food wit/person/W (%)

Lime Celery Parsley Parsnip Grapefruit Lemon carrot @ais

1.276 (97.41) 0.023 (1.76) 0.004 (0.3 I) 0.003 (0.23) 0.003 (0.23) 0.001 (0.08)

<O.OOl (0.01) <O.OOl (0.01)


TABLE I

DIETARYFLJROCOUMARINEXPOSUREBYPOPULATIONGROUP

Furocoumarin intake @idpe~n/b9

Distribution factor N Mean SE

Age O-5 6-10

11-15 16-20 21-25 26-30 31-35 36-40 41-45 46-50 51-55 56-60 61-65 66-10 71-75 76-80 81-85 86-90

Race White Black Asian/Pacific Native Americans Other races

Sex Female Male

Total population Overall mean Overall standard error

707 0.86 0.12 687 1.10 0.13 599 1.64 0.19 538 2.48 0.30 526 2.02 0.26 712 2.19 0.34 699 1.44 0.22 656 1.58 0.23 494 1.12 0.17 458 1.10 0.17 404 0.90 0.18 405 0.75 0.15 466 0.53 0.11 380 0.53 0.10 280 0.69 0.18 158 0.77 0.26 90 0.39 0.19 52 0.52 0.29

7,020 1.21 0.05 899 2.28 0.24

92 2.99 1.50 85 3.29 0.91

201 2.01 0.35

4,505 3,806

8,311

1.17 0.06 1.47 0.09

1.31 0.05

in the food intake survey ate furocoumarin-containing food. It is likely, however, that all people ingest furocoumarins even though the level may not be measurable by present analytical methods or the exposure may not be represented by a 3day sampling period.

Furocoumarin intake is distributed over all age, race, and sex groups. As shown in Table 7, exposure is greatest in the latter teen years and in the early years of adulthood when carbonated beverages are consumed heavily. Nonwhite races seem to have higher dietary exposure, but the significance of this is unknown. The small difference between the sexes disappears when differences in body weight are considered.

There are a number of other types of sources in addition to dietary sources. Pho- todermatitis is an occupational hazard of farm workers and food processors who have


dermal exposure to furocoumarin-containing plants (Berkley et al., 1986). Children playing with some umbelliferous plants, especially the giant hogweed, also get photodermatitis (Smellie, 1968). Furocoumarins have been a problem in fragrances, cos- metics, and suntan preparations (Kaidbey, 1987). In addition, furocoumarins are used therapeutically in dermatology.

Residues of furocoumarins occur in foods of animal origin such as meat, milk, and eggs. Plants of Umbelliferae, Rutaceae, or furocoumarin-containing genera of other plant families present in the environment of grazing animals are eaten in time of starvation, if not at other times. Examples are photosensitization of goats in West Texas that ingested Thamnosma texana (Oertli et al., 1983) and geese in Israel that ingested Ammi m&s (Eilat et al., 1974). Clinical intoxication is evidence of the presence of furocoumarin in the animal tissues. Thus people are exposed to large numbers of furocoumarin compounds that do not occur in plants eaten by humans.

Assessments based on a limited number of samples of highly variable materials should be interpreted with care. Exposure estimates have three major components: concentration of furocoumarin in food plants, percentage of these plants in food dishes eaten, and quantity of each food eaten. Each of these three factors has a variance, but the exposure calculations used only the variance for amount of each food eaten. The variances for the other two factors are not currently available. The true exposure may be an order of magnitude lower or higher than the estimate of 1.3 mg per person per day; i.e., it may be as low as 0.13 mg or as high as 13 mg.

In addition to a paucity of chemical analyses for statistically valid samples and a lack of ingredient data for minor components of foods such as herbs, spices, and natural flavorings, a second set of issues involves the large variances in concentration of secondary metabolites. Furocoumarins are only one of a large group of these natural defensive chemicals. They are not involved in the structure and function of the un- challenged organism but are part of adaptive processes which enable the organism to survive unfavorable conditions. Factors which enhance furocoumarin production in- clude genetic strain, cold, treatment with hypochlorite or copper sulfate, prolonged storage, and fungal disease (Beier and Oertli, 1983; Chaudhary et al., 1985; Trumble et al., 1990). But stress does not always lead to increased levels; e.g., herbicide treatment, which usually enhances defense, decreased furocoumarin concentration in Cymopterus watsonii (spring parsley) (Williams and James, 1983). Many of the same stresses that are in the growing fields and commercial channels also exist in the kitchen environment. Cooking does not destroy furocoumarin (Ivie et al., 198 1).

CONCLUSIONS

No definitive conclusion can yet be drawn that the overall effect is either detrimental or beneficial to public health. The same food may contain both carcinogens and anticarcinogens and even the same chemical may have both carcinogenic and anticar- cinogenic actions under different circumstances. Aflatoxins and furocoumarins have many similarities, but further information and evaluation are needed to determine whether measures to control furocoumarins are needed. Dietary exposure to furocoumarins can be controlled by proper selection of genetic strains of plants and reduction of stress during growing, storage, and processing of food. Research priorities should emphasize limes over other foods.

Furocoumarins are probably the norm and not the exception in plant defensive


systems. They should not be viewed in isolation from other food safety factors. Only plant types which can defend themselves against their competitors have survived. If a plant is to continue to survive, it must compensate for the reduction of one defense by enhancing other defensive means.

REFERENCES

BEIER, R. C. (1990). Natural pesticides and bioactive components in foods. Rev. Environ. Contum. Toxicol. 113,47-137.

BEIER, R. C., AND OERTLI, E. H. (1983). Psoralen and other linear furocoumarins as phytoalexins in celery. Phytochemistry 22, 2595-2597.

BEIER, R. C., IVIE, G. W., OERTLI, E. H., AND HOLT, D. L. (1983). HPLC analysis of linear furanocoumarins (psoralens) in healthy celery (Apium gruveoIens). Food Chem. Toxicol. 21, 163-165.

BERKLEY, S. F., HIGHTOWER, A. W., BEIER, R. C., FLEMING, D. W., BROKOPP, C. D., IVIE, G. W., AND BROOME, C. V. (1986). Dermatitis in grocery workers associated with high natural concentrations of furanocoumarins in celery. Ann. Intern. Med. 105, 35 I-355.

BLACK, H. S., YOUNG, A. R., AND GIBES, N. K. (1989). Effects of butylated hydroxytoluene upon PUVA- tumorigenesis and induction of omithine decarboxylase activity in the mouse. J. Photochem. Photobiol. B 3,91-100.

CARTWRIGHT, L. E., AND WALTER, J. F. (1983). Psoralen-containing sunscreen is tumorigenic in hairless mice. J. Am. Acad. Dermatol. 8.830-836.

CESKA, O., CHAUDHARY, S. K., WARRINGTON, P. J., AND ASHWOOD-SMITH, M. J. (1986a). Furocoumarins in the cultivated carrot, Daucus carota. Phytochemistry 25, 8 l-84.

CESKA, O., CHAUDHARY, S. K., WARRINGTON, P. J., POULTON, G., AND ASHWOOD~MITH, M. J. (1986b). Naturally-occurring crystals of photocarcinogenic furocoumarins on the surface of parsnip roots sold as food. Experientia 42, 1302- 1304.

CESKA, O., CHAUDHARY, S. K., WARRINGTON, P. J., AND ASHWOODSMITH, M. J. (1987). Photoactive furocoumarins in fruits of some umbellifers. Phytochemistry 26, 165-169.

CHAUDHARY, S. K., CESKA, O., WARRINGTON, P. J., AND ASHWOOD-SMITH, M. J. (1985). Increased furocoumarin content of celery (Apium graveolens var. d&e) during storage. J. Agric. Food Chem. 33, 1153-1157.

Chemical Abstracts Service (I 985). Registry Hundbook-Common Names. American Chemical Society, Columbus, OH.

COFFMAN, K., BOYCE, W. T., AND HANSEN, R. C. (1985). Phytophotodermatitis simulating child abuse. Am. J. Dis. Child. 139, 239-240.

DUNNICK, J. K. (1989). NTP Technical Report on the Toxicology and Carcinogenesis Studies of 8-Meth- oxypsoralen (CAS No. 298-81-7) in F344/N Rats (Gavage Studies). Publication No. 89-2814. National Institutes of Health, Bethesda, MD.

EILAT, A., MALKINSON, M., SHLOSBERG, A., AND EGYED, M. N. (1974). A field outbreak of photosensitization in goslings caused by the ingestion of Ammi majus. Refu. Vet. 31,83-86.

FISHER, J. F., AND TRAMA, L. A. (1979). High-performance liquid chromatographic determination of some coumarins and psoralens found in citrus peel oils. J. Agric. Food Chem. 27, 1334- 1337.

GRAY, A. I., AND WATERMAN, P. G. (1978). Coumarins in the Rutaceae. Phytochemistry 17, 845-864. GROSS, T. P., RATNER, L., DE RODREIGUEZ, O., FARRELL, K. P., AND ISRAEL, E. (1987). An outbreak of

phototoxic dermatitis due to limes. Am. J. Epidemiol. 125, 509-5 14. IPPEN, H. (1982). [Photoxic reaction to figs.] Hauturzt 33, 337-339. IVIE, G. W., HOLT, D. L., AND IVEY, M. C. (198 1). Natural toxicants in human foods, psoralens in raw and

cooked parsnip root. Science 213, 909-9 10. IVIE, G. W., BEIER, R. C., AND HOLT, D. L. (1982). Analysis of the garden carrot (Duucus carom L.) for

linear furocoumarins (psoralens) at the sub parts per million level. J. Agric. Food Chem. 30,4 13-4 16. KAIDBEY, K. (1987). The evaluation of photoallergic contact sensitizers in humans. In Dermatotoxicology,

(F. N. Marzulli and H. I. Maibach, Eds.), 3rd ed. National Academy of Sciences, Washington, DC. MABBERLEY, D. J. (1989). The Plant-Rook. Cambridge Univ. Press, Cambridge, UK. OERTLI, E. H., ROWE, L. D., LOVERING, S. L., IVIE, G. W., AND BAILEY, E. M. (1983). Phototoxic effect

of Thamnosma texana (Dutchman’s breeches) in sheep. Am. J. Vet. Res. 44, 1126-l 129. OPDYKE, D. L. J. (1974). Monographs on fragrance raw materials. Food Cosmet. Toxicol. 12, 703-736.


PATHAK, M. A., DANIELS, F., AND FITZPATRICK, T. B. (1962). The presently known distribution of furocoumarins (psoralens) in plants. J. Invest. Dermatol. 39,225-239.

PETERKIN, B. B., RIZEK, R. L., AND TIPPET-~, K. S. (1988). Nationwide food consumption survey, 1987. Nutr. Today 23, 18-24.

SHU, C. K., WALDRADT, J. P., AND TAYLOR, W. I. (1975). Improved method for bergapten determination by high-performance liquid chromatography. J. Chromatogr. 106, 27 l-282.

SMELLIE, J. H. (1968). Giant hogweed. Br. Med. J. 3, 123. STADLER, E., AND BUSER, H. R. (1984). Defense chemicals in leaf surface wax synergistically stimulate

oviposition by a phytophagous insect. Experientia 40, 1157-l 159. STANLEY, W. L., AND JURD, L. (197 1). Citrus coumarins. J. Agric. Food Chem. 19, 1106-l 110. STANLEY, W. L., AND VANNIER, S. H. (1967). Psoralens and substituted coumarins from expressed oil of

lime. Phytochemistry 6, 585-596. STERN, R. S. (1990). Genital tumors among men with psoriasis exposed to psoralens and ultraviolet A

radiation (PUVA) and ultraviolet B radiation. New Engl. J. Med. 322, 1093-1097. TRUMBLE, J. T., DERCKS, W., QUIROS, C. F., AND BEIER, R. C. (1990). Host plant resistance and linear

furanocoumarin content of Apium accessions. J. Econ. Entomol. 83, 5 19-525. VOLDEN, G., KROKAN, H., KAVLI, G., AND MIDELFART, K. (1983). Phototoxic and contact toxic reactions

of the exocarp of sweet oranges: A common cause of cheilitis? Contact Dermatitis 9,20 l-204. WAGSTAFF, D. J. (1985). The use of epidemiology, scientific data, and regulatory authority to determine

risk factors in cancers of some organs of the digestive system. 3. Liver cancer. Regul. Toxicol. Pharmacol. 5,384-404.

WAGSTAFF, D. J. (1990). Checklist of carcinogenic and poisonous plants. Submitted for publication. WILLIAMS, M. C., AND J-ES, L. F. ( 1983). Effects of herbicides on the concentration of poisonous compounds

in plants: A review. Am. J. Vet. Res. 44, 2420-2422. ZAYNOUN, S., ALI, L. A., TENEKJIAN, K., AND KURBAN, A. (1985). The bergapten content of garden parsley

(Petroselinum sativum) and its significance in causing cutaneous photosensitization. Clin. Exp. Dermatol. 10.328-33 1.

dietary exposure to furocoumarins

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