Carcinogenicity and Pesticides - American Chemical Society

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Chapter 3

Pathogenesis of Neoplasia and Influences of Pesticides Gary M. Williams American Health Foundation, 1 Dana Road, Valhalla, NY 10595 The evolution of a neoplasm i s a complex m u l t i -event and multi-stage process which proceedes through two sequences, the conversion of normal c e l l s to neoplastic c e l l s and the development of neoplastic c e l l s into tumors. These sequences have been documented experimentally to be s i m i l a r i n a number of tissues affected by chemical carcinogens. The c e l l u l a r events i n experimental carcinogenesis also have t h e i r counterparts i n human cancer development. Chemi c a l s , including p e s t i c i d e s , affect the carcinogenic process i n a v a r i e t y of ways, both facilitory and i n h i b i t o r y , i n the sequences of neoplastic conversion and development. Some chemicals exert more than one e f f f e c t on the neoplastic process.

The pathogenesis of chemically-induced cancer i s complex, cons i s t i n g of a series of events. The process can be divided into two d i s t i n c t sequences, neoplastic conversion, involving change i n the genetic apparatus of c e l l s leading to generation of a neoplastic c e l l and neoplastic development i n which the neoplastic c e l l evolves into a tumor (Fig 1). In experimental models, pesticides can influence both sequences, either enhancing or i n h i b i t i n g them. Chemical Carcinogens Chemical carcinogens are defined operationally by t h e i r ability to produce an increase i n tumor incidence. Chemicals capable of eliciting a tumor response i n experimental animals comprise a highly diverse c o l l e c t i o n of s t r u c t u r a l types of chemicals ( 1 ) . Considering t h i s fact alone, i t has seemed l i k e l y that the tumorigenic effects of carcinogens could be exerted by several mechanisms. Evidence of t h i s i s provided by observations that, a l 0097-6156/89/0414-0033$06.00/0 © 1989 American Chemical Society Ragsdale and Menzer; Carcinogenicity and Pesticides ACS Symposium Series; American Chemical Society: Washington, DC, 1989.


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CARCINOGENICITY AND PESTICIDES

Neoplastic Conversion

Neoplastic Development

Chemical Carcinogen

Neoplastic Cell

DNA Reaction

Promotion

Epigenetic Effects Progression

DNA Alteration Expression Figure 1.

Neoplasm

Outline of the carcinogenic process.

Ragsdale and Menzer; Carcinogenicity and Pesticides ACS Symposium Series; American Chemical Society: Washington, DC, 1989.

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Pathogenesis of Neoplasia and Influences of Pesticides 35

though many carcinogens give r i s e to reactive species that damage DNA, some carcinogenic chemicals, notably hormones, do not have these properties. In recognition of t h i s fundamental difference, a mechanistic categorization of carcinogens into two main types, DNA-reactive and epigenetic, (Table I) has been developed (2). Table I .

C l a s s i f i c a t i o n of Carcinogens


Type of Carcinogen DNA-reactive (Genotoxic) Activation-independent Act ivat ion-dependent Inorganic Epigenetic Promoter Hormone-modifying Immunosuppressor Cytotoxic Peroxisome p r o l i f e r a t o r Unclassified

Example of type

Alkylating agent P o l y c y c l i c aromatic hydrocarbon, nitrosamine metal

organochlorine compounds saccharin, drugs amitrole purine analog nitritotriacetate lactofen methapyrilene

The d i s t i n c t i o n between DNA-reactive or genotoxic carcinogens and the epigenetic type i s important to the understanding of the influences of pesticides on the pathogenesis of neoplasia, since there are major differences between the two types i n chemical actions and mechanisms. The Neoplastic Process The neoplastic phenotype i s transmitted to the progeny of neoplast i c c e l l s and thus must involve a change i n the structure or expression of genetic information. DNA-reactive carcinogens are capable of effecting such an a l t e r a t i o n d i r e c t l y through a mutat i o n a l event, either in base sequences or gene arrangement. In contrast, epigenetic agents may act either by f a c i l i t a t i n g expression of a preexisting abnormal genome or by inducing an abnormal genome through: 1) spontaneous mutation during increased levels of induced c e l l p r o l i f e r a t i o n ; 2) induced mutation through impairment of the f i d e l i t y of DNA polymerases; 3) induction of a stable a l tered state of gene expression; or A) generation of i n t r a c e l l u l a r reactive species such as activated oxygen, which are i n turn genotoxic. The sequence of events by which chemicals produce cancer from t h e i r action on normal c e l l s i s outlined i n Figure 1.


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Biotransformation Certain synthetic DNA-reactive carcinogens have chemical r e a c t i v i t y inherent i n t h e i r structures and are referred to as d i r e c t - a c t i n g , primary, or activation-independent carcinogens. Apart from these, most DNA-reactive carcinogens require biotransformation by host enzyme systems into reactive metabolites and, accordingly, are designated as i n d i r e c t , secondary, procarcinogens or activâtion-dependent carcinogens. Biotransformation results from the operation of enzyme systems involved i n the metabolism of endogenous substrates, but which can also act on xenobiotics. The p r i n c i p a l enzymes that biotransform chemicals are part of the cytochrome P-450 dependent monooxygenase system associated with the endoplasmic reticulum. For a l l classes of genotoxic carcinogens, except nitrosamines, most metabolic steps generate detoxified water-soluble metabolites which can be excreted, usualy i n the form of conjugates. Thus, the metabolism of carcinogens to activated forms i s a minor byproduct of biotransformation. One reaction, sulf©conjugation, i s detoxifying f o r C-OH compounds, but a c t i v a t i n g f o r N-OH compounds. A few a c t i v a t i o n reactions, such as N-oxidation, acetylation, or n i t r o reduction can be performed by enzymes other than those of the cytochrome system. Most biotransformation takes place i n the l i v e r , with other organs involved to varying degrees (3). Certain b a c t e r i a l enzymatic actions, such as glucoside cleavge, n i t r o reduction, and azo reduction for certain tetrazo dyes, are involved i n the a c t i v a t i o n of compounds i n the i n t e s t i n e . For many epignetic carcinogens, such as hormones and organochlorine p e s t i c i d e s , metabolism leads to detoxified products. However, an a c t i v a t i o n reaction metabolizes certain immunosuppressants to t h e i r cytotoxic forms. I t has been suggested that induct i o n of a P-452 oxidation of f a t t y acids may underlie the a b i l i t y of agents to induce peroxisomes (4). The l a t t e r event, i s believed to underlie the carcinogenicity of peroxisome p r o l i f e r a t o r s (5), among which are some pesticides (6). Major differences exist between species i n biotransformation processes. For example, most animal species display either rapid (e.g. hamster) or slow (e.g. r a t ) acetylation a c t i v i t y , whereas humans are endowed with a g e n e t i c a l l y determined polymorphism (7). Differences i n biotransformation a c t i v i t i e s account f o r many d i f ferences i n s u s c e p t i b i l i t y to carcinogenesis. For example, i t has been demonstrated that differences i n acetylation a c t i v i t y i n fluence the genotoxicity of aromatic amines (8). A variety of chemicals modify biotransformation processes (9). Among these are a number of organochlorine pesticides, such as DDT, which induce l i v e r enzyme activités. In general, such pest i c i d e s i n h i b i t the carcinogenicity to experimental animals of activâtion-dependent carcinogens.


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Pathogenesis of Neoplasia and Influences ofPesticides

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Ultimate Carcinogen


For organic d i r e c t - a c t i n g carcinogens and activated metabol i t e s of procarcinogens, the ultimate reactive form of these genotoxic carcinogens i s an e l e c t r o p h i l i c reactant (10). For epigenetic carcinogens, i t i s also possible that reactive species could be generated from normal c e l l u l a r consitituents. Hydrazine has been reported to give r i s e a methylating species (11.). Peroxisome p r o l i f e r a t o r s appear to lead to generation of reactive oxygen species as a r e s u l t of production of H2O2 during oxidation of l i p i d s i n peroxisomes (5). Macromolecular Interactions The ultimate e l e c t r o p h i l i c forms of DNA-reactive carcinogens can react covalently with nucleophilic s i t e s i n protein, RNA and DNA (12). Glutathione i s also a good nucleophile i n competition with other molecules. Binding to proteins, because of t h e i r r e l a t i v e abundance i n c e l l s , i s usually the major macromolecular i n t e r action of carcinogens. As a result of reaction with DNA, carcinogens of t h i s type are mutagenic and active i n other short-term tests for carcinogens (13). The ultimate e l e c t r o p h i l i c reactants of carcinogens can bind to a l l four bases of DNA as well as to the phosphodiester backbone (14) . The base adducts are formed at several s i t e s , with the most susceptible s i t e appearing to be the purine nitrogen, e.g., nitrosamines a l k y l a t e guanine at the N7 p o s i t i o n and, to a lesser extent, the 06 p o s i t i o n . A f l a t o x i n B^ binds at the N7 p o s i t i o n of guanine, 2-acetylaminofluorene interacts at the C8 and N2 positions, and benzo(a)pyrene i s bound to the N2 p o s i t i o n . Biomonitoring approaches have demonstrated DNA-bound products i n humans exposed to enviornmental genotoxic carcinogens (13). Considerable evidence now indicates that binding to DNA i s a c r i t i c a l reaction of carcinogens (1,14) as implied i n the c l a s s i f i c a t i o n of such carcinogens as DNA-reactive or genotoxic. With a l k y l a t i n g agents, 06 a l k y l a t i o n appears to be highly relevant to the carcinogenic e f f e c t , and with benzo(a)pyrene the binding of the trans-7,8-dihydrodiol-9,10-epoxide to guanine seems to be the key reaction. The p a r t i c u l a r regions of DNA i . e . , the s p e c i f i c genes whose modification i s e s s e n t i a l to i n i t i a t i o n of the carcinogenic process are begining to be i d e n t i f i e d , as discussed below. Several carcinogenic pesticides are known to be DNA-reactive, for example, ethylene dibromide. Most, however lack t h i s a c t i v i t y (15) . For some types of epigenetic carcinogens, such as hormones (Table 1), noncovalent binding to s p e c i f i c c e l l u l a r receptors i s undoubtedly e s s e n t i a l to t h e i r oncogenic e f f e c t s . Effects on c e l l membranes may underlie the action of carcinogens that operate as tumor promoters. For the organochlorine pesticides that act as tumor promoters (see below), such e f f e c t s on c e l l membranes may be critical.


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DNA Repair The damage produced i n DNA by genotoxic carcinogens can be corrected, primarily by repair process i n which the damage or the region containing the damage i s removed ( .14 ). In the excision type of repair, an i n c i s i o n i s made by an endonuclease i n the DNA strand i n the v i n i c i t y of the DNA damage, a stretch of DNA containing the region of damage i s excised, and a patch i s synthesized, followed by r e j o i n i n g of the strand. One type of excision repair, nucleotide excision i s e l i c i t e d by the i n troduction of bulky adducts into DNA and may r e s u l t i n the removal of 80-100 nucleotides per adduct. Another type, base excision i s provoked by smaller modification of bases such as a l k y l a t i o n and usually involves the removal of only 3-4 bases surrounding the damaged region. An additional type of repair i s the removal the a l k y l group from 06-alkylguanine by the 06-alkylguanine-DNAalkyltransferase system. Different types of damage are repaired at d i f f e r e n t rates; thus, the C8-guanine adduct of 2-acetylaminoluorene and other aromatic amines i s removed at a considerably faster rate than the N2 adduct, perhaps because the l a t t e r does not lead to major denaturation of the double h e l i x . In addition, s i g n i f i c a n t species and t i s s u e differences i n rates of repair e x i s t . For example, damage to l i v e r DNA by dimethylnitrosamine i s more slowly repaired i n the hamster than i n the r a t . In mice and r a t s , the residues of 06-alkylguanine produced by ethylnitrosurea i n l i v e r and kidney are rapidly removed, whereas a l k y l a t i o n i s highly persistent i n brain. The a c t i v i t y of the alkyltransferase system i s inducible. In general, humans are more p r o f i c i e n t i n DNA repair processes than animals, although genetically-determined deficiency states, such as xeroderma pigmentosum, occur. Altered E f f e c t o r Considerable evidence now indicates that the e f f e c t o r f o r neoplastic conversion of c e l l s i s DNA. I f the damage to DNA by a genotoxic carcinogen i s not repaired and the affected region i s used as the template f o r synthesis of new DNA, a permanent mutation can be introduced through mispairing of bases. Because of t h i s rapidly p r o l i f e r a t i n g tissues and those stimulated to p r o l i f e r a t e are highly susceptible to carcinogens. Several types of damage to DNA are now known to be promutagenic (.16). For example a l k y l a t i o n of the 06 p o s i t i o n of guanine r e s u l t s i n base p a i r i n g with thymine rather than cytosine (17). The nature of the permanently a l t e r e d e f f e c t o r that i s c r i t i c a l to neoplastic conversion increasingly appears to involve act i v a t i o n of c e l l u l a r oncogenes (14,18,19), see below. S p e c i f i c mutations i n oncogenes have been i d e n t i f i e d (19), as well as other changes. These occur i n oncogenes i s o l a t e d from neoplasms a r i s i n g in both experimental animals and humans (20,21). Co-Carcinogenicity The phenonmenon of co-carcinogenicity i s the enhancement of carcinogenicity of a chemical by another concurrently administered chemical, which, under the test conditions, i s not i t s e l f car-


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Pathogenesis of Neoplasia and Influences of Pesticides

39

cinogenic (22). Several mechanisms are possible for the action of co-carcinogens and i t seems l i k e l y that d i f f e r e n t mechanisms operate i n s p e c i f i c s i t u a t i o n s . A p e s t i c i d e operating as a cocarcinogen has not been described. Agents believed to operate as co-carcinogens i n humans i n clude tobacco smoke and alcohol (23). No evidence e x i s t s for a co-carcinogenic action of pesticides i n humans.


Neoplastic C e l l s Neoplastic c e l l s have an altered genome, including both DNA and chromosomal mutation. The e s s e n t i a l b i o l o g i c a l abnormality i n neoplastic c e l l s i s a loss of growth c o n t r o l . Certain l i n e s of evidence suggest that the neoplastic state i s a homozygous recessive condition (24), which may r e f l e c t i n a c t i v a t i o n of a n t i oncogenes. Other studies point to the a c t i v a t i o n of dominant c e l l u l a r oncogenes (25). The function of anti-oncogenes i s not understood, but i t i s well-established that oncogenes code for factors involved i n c e l l u l a r growth (26,27). The neoplastic c e l l may p e r s i s t i n a dormant state f o r months, i n s p i t e of genetic a l t e r a t i o n s , or, depending upon host conditions, grow to form a neoplasm. The elements which prevent expression of i n i t i a t e d c e l l s as neoplasms are not understood, but may involve f a c t o r s , such as chalones, which regulate growth and d i f f e r e n t i a t i o n . Large molecules can be exchanged between c e l l s through s p e c i a l i z e d membrane structures known as gap junctions. Thus, transmission of regulatory factors from normal to i n i t i a t e d c e l l s may e f f e c t control of the l a t t e r . The c e l l s of f u l l y developed neoplasms are d e f i c i e n t i n gap junctions and possess other membrane abnormalities, i n d i c a t i n g a l i m i t a t i o n i n t h e i r a b i l i t y to receive regulatory signals. Promotion The c l a s s i c a l d e f i n i t i o n of promotion i s the enhancement of the carcinogenicity of an agent by a second agent, not carcinogenic by i t s e l f under the t e s t conditions, acting a f t e r exposure to the f i r s t has ended (22). In experimental animals, promotion has been shown to occur i n most organs, including skin, l i v e r , stomach, colon, breast, and bladder (28). Although promoters are usually regarded as being noncarcinogenic, most w i l l i n fact e l i c i t tumor formation a l b e i t i n small y i e l d , when administered alone under conditions of prolonged exposure at high l e v e l s . This i s probably the basis for the carcinogenicty of agents such as saccharin and c e r t a i n organochlorine pesticides (Table I ) . A v a r i e t y of e f f e c t s have been suggested to underlie the promoting action of chemicals (9). Since i n i t i a t e d c e l l s can remain dormant i n tissues for many months, i t seems evident that these altered c e l l s are being kept under some kind of growth regulation. As described above, c e l l s exchange l a r e molecules through membrane gap junctions. I f t h i s kind of i n t e r c e l l u l a r exchange i s involved i n the regulation of d i f f e r e n t i a t i o n and growth, then interference with t h i s process could release dormant tumor


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c e l l s f o r growth into neoplasms. Thus, tumor promotion may be explained by interference with the growth control suppression of latent tumor c e l l s . A large number of tumor promoters have now been demonstrated to have the a b i l i t y to i n h i b i t i n t e r c e l l u l a r com* munication (29), and therefore, t h i s e f f e c t i s assuming importance as one basis f o r tumor promotion. Several organochlorine pesticides have been documented to be l i v e r tumor promoters i n experimental animals (Table I I ) . An i n teresting species difference i s that hamsters were found to be r e s i s t a n t to DDT promotion (32). Agents believed to operate as promoters i n humans include tobacco smoke, hormones and b i l e acids (23). No evidence exists for a promoting action of pesticides i n humans. Table I I .

L i v e r Neoplasm Promotion by Organochlorine Pesticides

Pesticide

Species

Effect

Reference

DDT

rat mouse hamster mouse mouse

+ +

30 31 32 31 31

Chlordane hepatchlor

-

+ +

Progression Neoplasms can undergo permanent stable changes i n t h e i r phenotype, a process referred to as progression (33). L i t t l e i s known about the basis f o r t h i s a l t e r a t i o n i n the c h a r a c t e r i s t i c s of neoplasms. I t could r e s u l t from gene amplification or a change i n t h e i r chromosomal complement. Another hypothesis (34) i s that decreased f i d e l i t y of DNA polymerases i n tumor c e l l s leads to errors i n the r e p l i c a t i o n of DNA, thereby introducing new mutations. Conclusions As detailed, the o v e r a l l carcinogenic process i s complex and involves a series of steps comparising two d i s t i n c t sequences. B a s i c a l l y , the process i s s i m i l a r i n experimental animals and i n humans. In f a c t , several chemical carcinogens have been shown to exert s i m i l a r e f f e c t s , such as the type of DNA adduct and type of neoplasm, i n both animals and humans. Nevertheless, there are d e f i n i t e quantitative differences between species of animals and between experimental animals and humans. These differences make s i m p l i s t i c mathematical extrapolation of animal data to p o t e n t i a l human e f f e c t s a n o n - s c i e n t i f i c enterprise (35). Most chemicals that have caused cancer i n humans are of the DNA-reactive type (35-37). Given s u f f i c i e n t exposure, i t seems l i k e l y that any experimental carcinogen of t h i s type would produce cancer i n humans. Many have not (38), however, which may be due to



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Pathogenesis of Neoplasia and Influences of Pesticides 41

the defense mechanisms (i.e. chemical detoxification and DNA repair processes) with which humans are endowed. Regardless, carcinogens of this type should be regarded as qualitative hazards (36). Few experimental carcinogens of the epigenetic type have been associated with cancer in humans, these are mainly hormones or im munosuppressants. Humans have been exposed to many pesticides known to cause cancer in experimental animals, but none has been linked to cancer in humans (38). The absence of effects in humans has been suggested to be due the fact that exposures of humans are below the threshold for the biological effect (e.g. peroxisome proliferation or membrane alteration and consequent promoting ac tion) underlying carcinogenicity (36). Moreover, some of the con ditions necessary for tumor induction in rodents may not be at tainable or tolerable to humans. References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15.

Searle, C.E. Chemical Carcinogens; American Chemical Society:Washington, DC, 1984; 2nd ed., ACS Monograph 182. Williams, G.M.; Weisburger, J . H . , In Toxicology. The Basic Sciences Of Poison; Klaassen, C . , Amdur, M., Doull, J.; MacMillan:New York, 1986; 3rd ed. p. 99. Weisburger, J . H . ; Williams, G.M., In Cancer: A Comprehensive Treatise; Becker, F . F . Ed.; Plenum Press:New York, 1982; 2nd ed., p. 241. Sharma, R.; Lake, B.G.; Foster, J.; Gibson, G.G. Biochem. Pharmacol. 1988, 37, 1193-1201. Rao, M.S.; Reddy, J.K. Carcinogenesis 1987, 8, 631-36. Butler, E . G . ; Tanaka, T . ; Ichida, T . ; Maruyama, H . ; Leber, A.P.; Williams, G.M. Toxicol. Appl. Pharmacol. 1988, 93, 72-80. Weber, W.W. The Acetylator Genes And Drug Response; Oxford University Press:New York, 1987. McQueen, C.A.; Maslansky, C . J . ; Williams, G.M. Cancer Research 1983, 43, 3120-23. Williams, G.M. Fundamental and Applied Toxicology 1984, 4, 325-44. Miller, E . ; Miller J . In Origins of Human Cancer; Hiatt, , Watson, , Winsten, , Eds.; Cold Spring Harbor Laboratories:New York, 1977; p. 605. Bosan, W.S.; Shank, R.C. Toxicol. Appl. Pharmacol. 1983, 70, 324-34. Williams, G.M.; Weisburger, J.H. In A Guide to General Toxicology; Homburger, F . , Hayes, J.A. Eds.; Karger:New York, 1983; Chapter 12. Williams, G.M. Ann. Rev. Pharmacol. Toxicol. 1989, 29, 189211. Weinstein, I . B . ; Vogel, H.J. Genes and Proteins in On cogenesis; Academic Press:New York, 1983. Williams, G.M. In The Pesticide Chemist and Modern Toxicol ogy. Bandai, S.Κ., Marco, G . J . , Golberg, L. and Leng, M.L. Eds.; American Chemical Society Symposium Series 160; American Chemical SocietyWashington, DC, 1981; p. 45.


42 16. 17.


18. 19. 20. 21. 22. 23.

24. 25. 26. 27. 28. 29.

30. 31. 32. 33. 34. 35.

36. 37. 38.

CARCINOGENICITY AND PESTICIDES Rossman, T.G.; Klein, C.B. Environ. Molec. Mutagen. 1988, 11, 119-33. Snow, E.T.; Foote, R.S.; Mitra, S. J. Biol. Chem. 1984, 259, 8095-100. Alitalo, K.; Koskinen, P.; Makela, T.P.; Saksela, K.; Sistonen, L . ; Winquist, R. Biochimica et Biophysica Acta 1987 907, 1-32. Bos, J.L. Mutation. Research. 1988,, 195, 255-71. Der, C.J. Clin. Chem. 1987, 33, 641-46. Nishimura, S.; Sekiya, T. J . Biochem. 1987, 243, 313-27. Berenblum, I. Carcinogenesis as A Biological Problem; Amreican Elsevier:New York, 1974. Williams, G.M. In Cancer of the Respiratory tract: Predisoposing Factors; Mass, M.J., Kaufman, D.G., Siegfried, J.M., Steele, V.E., Nesnow, S., Eds.; Raven Press:New York, 1985; p. 447 Harris, H. Cancer Research 1988, 48, 3302-6. Weinberg, R.A. Cancer 1988, 61, 1963-8. Heldin, C.H.; Betsholtz, C.; Claesson-Welsh, L . ; Westermark, B. Biochimica et Biophysica Acta 1987, 907, 219-44. Deuel, T.F. Ann. Rev. Cell. Biol. 1987, 3, 443-92. Slaga, T.J.; Sivak, Α.; Boutwell, R.K. Carcinogenesis: A Comprehensive Survey. Mechanisms of Tumor Promotion and Car cinogenesis; Raven Press:New York, 1983. Barrett, J.C.; Kakunaga, T.; Kuroki, T.; Neubert, D.; Trosko, J.E.; Vasiliev, J.M.; Williams, G.M.; Yamasaki, H. In LongTerm and Short-Term Assays for Carcinogens: A Critical Appriaisal Montesano, R., Bartsch, Η., Vainio, Η., Wilbourn, J . , Venitt, S. Eds.; IARC:Lyon, France, 1986, p. 287. Peraino, C.; Fry, R.J.; Staffeldt, E . ; Christopher, J. P. Cancer Res. 1975, 35, 2884-90. Williams, G.M.; Numoto, S. Carcinogenesis 1984, 5, 1689-96. Tanaka, T.; Mori, H.; Williams, G.M. Carcinogenesis 1987, 8, 1171-78. Foulds, L. Neoplastic Development; Academic Press:New York, 1969; Vol. 1. Springgate, C.F.; Leob, L.A. Proc. Nat. Acd. Sci. USA 1973, 70, 245-9. Williams, G.M.; Reiss, B.; Weisburger, J.H. In Mechanisms and Toxicity of Chemical Carcinogens and Mutagens; Flamm, G, Lorentzen, R. Eds.; Princeton Scietific Publishers:Princeton, NJ, 1985; Vol. 11, p. 207. Williams, G.M. In Banbury Report 25: Nongenotoxic Mechanisms in Carcinogenesis. Cold Spring Laboratory, 1987; p. 367. Williams, G.M.; Numoto, S. Carcinogenesis 1984, 5, 1689-96. Bartsch, H.; Malaveille, C. Cell Biol. Toxicol. 1989, 5, 000-000. International Agency for Research on Cancer. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans Overall Evaluations of Carcinogenicity: An Updating of IARC Monographs, Volumes 1-42, IARC:Lyon France, 1987.

RECEIVED August 14, 1989


Carcinogenicity and Pesticides - American Chemical Society

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