The Science o f the Total Environment, 4 (1975) 205-217 © Elsevier Scientific Publishing Company, Amsterdam - Printed in Belgium
THE CARCINOGENICITY
OF DIELDRIN.
P A R T II*
SAMUEL S. EPSTEIN Medical School, Case Western Reserve University, Cleveland, Ohio (U.S.A.)
(Received February 27th, 1975)
A. CHARACTERIZATION OF CARCINOGENS 1. D e f i n i t i o n
Carcinogens h a v e been defined b y myself a n d o t h e r witnesses in the cancellation hearing ( E D F Ex. 33, p. 7; E P A Ex. 40, p. 4; E P A Ex. 46, pp. 4-5), as chemical, physical o r b i o l o g i c a l agents, e x p o s u r e o f animals o r h u m a n s to which increases the p r o b a b i l i t y o f i n d u c t i o n o f benign o r m a l i g n a n t t u m o r s (neoplasms). This m a y m a n i fest as follows: "Increase in the tumor incidence in a given population, i.e., an increase in the number of tumor-bearing individuals. Increase in the number of tumors in each individual. Reduction in the latent period of tumor induction. Any combination of the above effects (EDF Ex. 33, p. 7)." The essential features o f this definition have been reiterated, as follows, b y each o f six successive expert c o m m i t t e e s o f the I n t e r n a t i o n a l Agency for Research in C a n c e r ( I A R C ) , in a series o f m o n o g r a p h s , published between 1972 a n d 1974, on the " E v a l u a t i o n o f C a r c i n o g e n i c Risks o f Chemicals to M a n " : "The response in experimental animals to a carcinogen may take several forms: (a) a significance increase in the incidence of one or more of the same types of neoplasms as found in control animals; (b) the occurrence of types of neoplasms not observed in control animals; (c) a decreased latent period as compared with control animals. "For present purposes, in general, no distinction is made between the induction of tumors and the enhancement of tumor incidence, although it is noted that there may be fundamental differences in mechanisms that will eventually be elucidated (IARC, 1974)." This s t a n d a r d definition o f c h e m i c a l carcinogens is p r a g m a t i c a n d depends on the r e c o g n i t i o n o f a n association between cause (or stimulus) and effect (or response). In no w a y is this definition influenced by the presence or absence o f i n f o r m a tion on the u n d e r l y i n g basic m e c h a n i s m s involved or b y the frequency o f occurrence o f s p o n t a n e o u s t u m o r s in u n e x p o s e d o r c o n t r o l animals o r humans. * Statement o f Testimony at Suspension Hearings on Aldrin/Dieldrin (Environmental Protection Agency and Environmental Defense Fund vs. Shell), September 1974. Part I appeared in Sci. Total Environ., 4 (1975) 1. Both statements were made by the author as witness to and consultant
for EPA and EDF. 205
2. On the alleged distinction between carcinogenic and "augmenting'" or "enhancing" or modifying" effects of Dieldrin a. Semantic nature of alleged distinctions Several of Shell's employee witnesses have stated that the induction o f an increased number of tumors in Dieldrin-treated mice is not sufficient to characterize Dieldrin as a carcinogen. This mythology implies what is essentially a new and highly restrictive concept of chemical carcinogens. Dr. Thorpe, for example ( E P A 42J, p. 440) invokes the concept of "the unknown oncogenic stimulus", supposed to be present in mice, and responsible for the observed incidence of " s p o n t a n e o u s " tumors, i.e., tumors in control or untreated mice. In his statement (p. 45), Dr. Thorpe maintained that compounds, such as Dieldrin and phenobarbital, may increase tumor incidence by "enhancing or augmenting an existing oncogenic stimulus" (author's emphasis). Dr. Thorpe further stated that "Empirical extrapolation (sic) of this phenomenon to other mammals is not tenable since there are no data to indicate that the causal agent of liver tumors in mice operates in other species." Dr. Wright (Statement, p. 26-27) similarly maintains, "Since tumors were observed in control mice, an oncogenic stimulus was present in these animals." Dr. Wright concludes from this (Statement, p. 27) that "faced with an increased incidence of 'control' tumors, current techniques and current understanding do not allow us to discriminate between an augmenting (co-carcinogenic) effect or a carcinogenic effect by Dieldrin or phenobarbitone... In my view, (this) factor is the most relevant to current issues..." The notion that a hypothetical "pre-existing oncogenic stimulus" must be excluded before a chemical can be considered carcinogenic is at variance with established definitions of chemical carcinogens (vide supra). Since in most cases it is impossible to rule out the existence of such an unknown factor, acceptance of the Shell position would consign most chemicals now classified as carcinogens to an indeterminate area--neither carcinogens nor non-carcinogens. Indeed, by contrived semantics, this might succeed in defining away the entire problem of chemical carcinogenesis. The inappropriateness of such a restrictive definition has been recently stressed b y Dr. Heston: "A carcinogen, therefore, should not be defined only as something that produces tumors in a strain in which tumors never occur without the carcinogen. Such a strain probably does not exist" (EPA Ex. 46, p. 5).
b. Dependence of the "Augmenting Factor" proposition on sample size T h e alleged distinction between carcinogens and "augmenting factors" hinges on the possibility of determining whether or not a certain type of tumor does occur " s p o n t a n e o u s l y " or not in the observed animal or human population. This possibility depends largely on the size of the population sample that can be examined. F o r cer206
tain rare human cancers, populations exceeding I0 million would have to be surveyed before a single instance could be identified. Illustratively, the approximate "spontaneous" incidence of angiosarcoma of the liver is 0.014 cases per million annually (IARC, 1974a), and is thus considered by the IARC committee to be a carcinogen. By Shell's definition, however, once the extremely rare, but nevertheless finite, background incidence of angiosarcomas was recognized, vinyl chloride would presumably be relegated to the category of an "augmenting agent." A less extreme example would be the observed effects of cigarette smoking, which, in the last few decades, has massively increased the incidence of a higher to comparatively low incidence of lung cancer. Cigarette smoke would presumably not be regarded as carcinogenic by the Shell employee witnesses, as "spontaneous" lung cancer does occur in non-smokers. c. On the alleged necessity for information on underlying mechanisms in ascribing the property of carcinogenicity to an agent Dr. Stevenson (Statement, p. 17) said that the association of Dieldrin with increased incidence of tumors in mice may simply reflect a "modifying effect" on the background incidence of tumors, and that elucidation of the underlying carcinogenic mechanism would be necessary before extrapolating this result toward the human situation. In cross-examination (STR-537), Dr. Stevenson admitted that Dieldrin feeding was associated with an increase in liver tumor incidence; five strains (CFI, C3H, Swiss-Webster, LACG, and the CF1 X LACG hybrid), but then continued,
"I am not prepared to say that this indicatesthat... Dieldrin is a carcinogen,per se, until I have further information indicatingthat there is a causal relationship." The basis for this question of mechanisms appears to be the well recognized fact that a wide range of environmental factors, or "biases", such as position in the animal room, cage type, diet and hormonal status can significantly influence the pattern of "spontaneous" tumors in untreated laboratory animal populations. The purpose of utilizing control animals in scientific experiments is precisely to eliminate or minimize all such environmental effects. The only effects difficult to control are those directly related to the experimental variable, e.g., a compound in the diet could affect total dietary intake, which has been shown to affect tumor frequencies. In this regard, I note that the Shell employee witness with overall scientific responsibility for the toxicology programs in Shell's Tunstall Laboratories, Dr. Stevenson, stated that they had tried to eliminate "biases" as much as possible in the various mouse tests on the carcinogenicity of Dieldrin, and admitted that he was unable to specify any other "biases". (STR.-465). The emphasis by Shell witnesses that knowledge of mechanisms must be defined before any agent can be considered carcinogenic, even though this agent has been demonstrated to induce carcinogenic effects in valid experimental systems, can only be regarded as misleading in extreme. In fact, in spite of a very considerable amount of research, the basic mechanisms of action of any single carcinogen have not yet been elucidated. This requirement of Shell would define away the entire field of chemical carcinogenesis. 207
3. On alleged distinctions between tumorigens and carcinogens Numerous expert individuals and national and international committees have unequivocally emphasized the invalidity of alleged distinctions between "tumorigens" and carcinogens and have emphasized that these terms are virtually synonymous (EDF, Ex. 33, pp. 28-31; EPA Ex. 40B, p. 12; EPA Ex. 40C, p. 16; EPA Ex. 40H, p. 2). One Shell witness, Dr. Coulston, has made the unsubstantiated allegation that this principle is obsolete and no longer accepted by cancer experts (STR.-1807). However, these concepts have been consistently reiterated by six recent IARC expert committees on chemical carcinogens. An IARC report published this year, states: "The qualitative nature of neoplasia has been much discussed. In many instances both benign and malignant tumors are induced by chemical carcinogens. There are so far few recorded instances in which only benign tumors are induced by chemicals that have been studied extensively.Their occurrence in experimental systems has been taken to indicate the possibility of an increased risk of malignant tumors also" (IARC, 1974). This consensus is in striking contrast with the statements of some Shell witnesses (STR-1430, 1480, 1482, 1542) who have attempted to develop poorly substantiated distinctions between carcinogens and tumorigens, the latter being alleged to be of less significance with regard to presumptive human cancer risk. However, this point is apparently not in serious contention, as Shell's principal current pathologist has explicitly rejected the tumorigen concept (Dr. Thorpe, Shell Ex. S-5, p. 23, and STR-1042). B. ON THE ALLEGED HIGH AND VARIABLE SPONTANEOUS TUMOR FREQUENCIES IN THE MOUSE LIVER At least two Shell witnesses have discounted the significance of the Dieldrininduced carcinogenicity data in the mouse on the alleged basis that the spontaneous appearance of hepatic tumors in the mouse is too high and/or too variable from strain to strain or, within the same strain, but on different occasions, for meaningful study (STR.-1248, 1249; Shell S 1, pp. 41-42). T o examine this contention, I have compiled a table on the incidence o f liver tumors in both Dieldrin-treated and control groups of CF1 mice, as reported in the various Tunstall Studies (Table 1). F r o m consideration of the frequencies of malignant hepatic neoplasms, as diagnosed by Shell's pathologists (type " b " tumors), it is apparent that their spontaneous incidence in control animals, particularly in the females, is neither high n o r variable, while the Dieldrin-treated groups consistently show marked and often high incidences of such malignancies. The association of "type b " neoplasms with Dieldrin feeding has never been of serious contention in these hearings. The frequencies of the "type a " tumors are more variable, as in fact would be expected. " T y p e a " is a Shell-suggested classification which presumably covers a wide range of histopathological conditions, including hyperplasia, pre-neoplastic lesions and liver nodules, the incidence of which is probably age-dependent. While Shell's studies report the maximum duration of each experiment, lifespan sfor individual 208
TABLE 1 INCIDENCE OF HEPATIC TUMORS (10 ppm Dieldrin in the diet) M I C E Study
Walker, et al., 1973 expt. 1 expt. 2.1 expt. 2.2
unsterilized diet irradiated diet irrad, diet & bed. expt. 2.3
I N CF1 C O N T R O L
% o f males
% of females
Controls
Treated
C o n t r o l s Treated
a
b
a
b
a
b
a
b
16 12
4 0
37 36
57 9
13 10
0 0
37 41
55 12
30 20 42 13
4 3 0 0
58 40 63
25 20 23 not
23 11 17 17
0 0 0 0
36 32 42
23 11 21
6 52 25
0 0 5
applicable expt. 2.4 Thorpe & Walker, 1973 Thorpe, 1974
AND TREATED
11 44 4
0 9 2
46 47 13
54 53 40
not applicable 66 40 7
22 47 66
animals are not specified on an actuarial basis. It is clear that both control and treated mice were dying throughout the experiments, especially in the period after 12 months, when new tumors progressively appear. In these circumstances, the number of tumors classified as "type a" at the time of death will depend critically on the lifespan of the animals, besides on other aspects of the experimental design. Under such conditions, it is likely that the frequencies of "type a" tumors will vary from experiment to experiment, unless comparisons are made on an age-adjusted basis. Despite this variability, Table 1 indicates that the frequency of "type a" tumors is clearly enhanced by Dieldrin treatment. The sole exception is among the females of the 1973 Thorpe and Walker study, in which "type b" tumors were increased from 0 to 47% by Dieldrin treatment. This left relatively few treated animals in which "type a" tumors could occur. The very purpose of controlled experiments, performed with adequate numbers of animals, as in Shell's Tunstall Studies, is to overcome natural biological variability and demonstrate effects, or their absence. Shell's own experiments clearly demonstrate how natural variability can be surmounted and an unequivocal result be obtained. The alleged high variability in the incidence of liver tumors in control mice has been used by Shell witnesses to challenge the role of mice in carcinogenicity testing. There are numerous statements in the literature, from a wide range of individual experts and expert national and international committees, substantiating the critical value of mice for carcinogenicity testing and for development of data which can be extrapolated to man (EDF Ex. 33, pp. 21-25). In this connection it is also important to note that the mouse is the standard reference test animal in recently established 209
and large scale H E W programs at the National Center for Toxicological Research, Pine Bluff, Ark., for quantitation of toxicologic and carcinogenic risk. Confidence in the mouse model for this purpose has been deafly stated by senior H E W spokesmen at recent Congressional hearings, illustratively, as follows (Schmidt, 1974): "The first large scale chronic study involving approximately 25,000 mice that was initiated on April 15 is not designed to find a threshold level of the carcinogen, 2-AAF. Rather, this experiment with over 700 different treatment groups is structured to produce experimental data that can be used for the development of improved mathematical models for quantitation of toxicologic and carcinogenic risk. Also, this experiment will provide reference data on chronic toxicity against which results attained using other testing methodologies can be compared." C. ON THE SUSCEPTIBILITY OF INFANTS TO CARCINOGENS It has been claimed, chiefly by Dr. van Raalte, that h u m a n babies are at no greater or even less risk to Dieldrin carcinogenesis than the general population, although their intake, on a body weight basis is greater than in adults ( B o m k a m p , EPA Ex. 38). Dr. van Raalte dismisses the fact that breast-fed babies in the first three months of life accumulate more Dieldrin on a b o d y weight basis, t h a n any other age group by saying, "the three-month period about which concern was expressed is only 1/284 or 0.35% of a lifetime." (My emphasis). H e further states that in babies, Dieldrin is "promptly stored.., in the lipid tissue.., and thus do(es) not give rise to an increasing concentration in the target tissues." Dr. van Raalte concludes that: "The question of whether the presently possible level of intake of Dieldrin by breast-fed babies is safe can.., only be answered in the affirmative" (Statement, pp. 54-58). This judgment appears both uninformed and irresponsible. N e w b o r n animals have been repeatedly demonstrated to be more sensitive to carcinogenic effects than adults. F o r these reasons, it has been widely recommended, including elsewhere, by a Shell witness, Dr. F. J. C. Roe (Roe et al., !961), that infant animals should be used in screening for chemical carcinogens (Della Porta, 1968; Epstein, et al., 1970; Health and Welfare, Canada, 1973). The following examples illustrate this enhanced sensitivity: (i) Aflatoxin B1 has not been shown carcinogenic in adult mice. However, when injected into 1-day-old animals of the same strain, h e p a t o m a s were induced by 52 weeks (Vesselixovitch et al., 1972). (ii) 3-Methylcholanthrene-induced lung tumors appeared 24 weeks following its injection in 2-week old mice. Such mice had six times the n u m b e r of tumors found in animals injected at 4 weeks, and 21 times the n u m b e r o f tumors in mice injected at 8 weeks of age ( O ' G a r a and Kelly, 1963). (iii) Urethane, a well-studied mouse carcinogen, has been shown to be m o r e carcinogenic when administered to newborn than adult mice (Liebelt et al., 1961). 210
In another study, urethane injected into newborn mice induced leukemia, while no comparable results were obtained with adult mice (Fiore-Donati et al., 1962). (iv) Dimethylnitrosamine, injected on a single occasion was found to be highly hepatocarcinogenic in mice, provided it was administered before the animals were 24 hours old. On the other hand, administration of the compound for 141 consecutive days, commencing at age of 5 weeks, failed to induce hepatic tumors (Toth et al., 1964). (v) Condensed cigarette smoke induced lung adenomas after a single injection in mice aged less than 12 hours (47% of the animals showed lung adenomas after 1 year). If injected at age 7 days, 40% of the animals showed lung adenomas after one year, while if injected at 14 days, only 20% of the animals showed the tumors after one year. Control animals had a lung adenoma rate of 1.5% (Flaks, 1966). (vi) Organic extracts of particulate atmospheric pollutants collected from various cities in the U.S.A. induced, in varying incidence, pulmonary adenomas, hepatomas and lymphomas following administration to infant mice (Epstein et al., 1966). With the exception of pulmonary adenomas, these tumors have not been reported following administration of extracts to mature mice. Dieldrin carcinogenicity has never been studied in neonatal animals. Dr. van Raalte's statement that Dieldrin is "promptly" stored in the fat of the "rapidly growinginfant.., and thus does not give rise to an increasingconcentrationin the target tissues" provides no evidence that infants would be any less susceptible to Dieldrin carcinogenicity than adults. Indeed, the converse seems more likely. In this connection, it is of interest to note that much experimental data, including some cited above, indicating the enhanced sensitivity to carcinogenicity relates to lipid-soluble carcinogens, which like Dieldrin tend to be selectively stored in body fat. There is no evidence whatsoever that such storage sequesters carcinogens and hence protects against chemical carcinogenesis. D. DIELDRIN AS AN IMMINENT HAZARD The issue in these suspension proceedings is whether the projected 1975 uses of Alddn/Dieldrin present an "imminent hazard" which would require immediate suspension of its major uses prior to the conclusion of the cancellation proceedings. The question thus posed is whether use of Dieldrin for one more year, 1975, would significantly increase carcinogenic hazards to man posed by existing environmental and body burdens. It has been estimated that the total sales of Aldrin/Dieldrin over the last 25 years in the U.S.A. approximates to 250 million pounds (Shell Ex. 111, Table I 1); the projected use of an approximate additional 10 million pounds in 1975 would thus constitute an increment of approximately 4% of the total burden of Dieldrin already introduced into the environment. 211
Testimony at these hearings (Fisher, Testimony at Suspension Hearings), has demonstrated that, where comparisons can possibly be made, it can be seen that residues of Dieldrin in food have not significantly changed in recent years. Thus, if a similar quantity of Aldrin/Dieldrin were to be used for similar purposes in 1975 as that which has been used annually over the past several years, it would be reasonable to assume that there would probably be no change in dietary residue levels. Further usage of Dieldrin for an additional year, 1975, would postpone b y one year the anticipated onset of the overall decline in the environmental burden o f Dieldrin and the consequent decline in levels of human exposure. The relevance to m a n of such a prolongation of Dieldrin exposure is amply demonstrated by experimental evidence from Shell's studies in mice (Walker et al., 1973, Study 2.4). These studies clearly indicate a positive relation between duration of exposure of mice to Dieldrin and the incidence of liver tumors (Table 2). The carcinogenic effects of Dieldrin, besides being dose-dependent, are thus also clearly time-dependent. Assuming that TABLE 2 T I M E - D E P E N D E N C Y OF D I E L D R I N E X P O S U R E O N C A R C I N O G E N I C EFFECTS IN MICE Duration o f feeding (Weeks)
No. mice ( M & F) with liver tumors (A & B)/Nos. at risk
% Incidence-liver tumors
0 2 4 8 16 32 64
3/43 4/22 5/22 8/22 7/19 8/20 21/22
9 18 23 36 37 40 95
humans and mice are similarly sensitive to the carcinogenic effects of Dieldrin--and there is no way of determining whether humans are more or less sensitive--then this striking time-dependency would also be expressed in humans. Further, assuming a similar pattern of time-dependency, relating duration of Dieldrin exposure a n d tumor incidence, in man as has been experimentally demonstrated in mice, then it is clear that the continued use of Dieldrin for a further year, 1975, would increase the carcinogenic hazard to man. The factor by which this hazard would be increased is currently indeterminate, though it would appear to be high, based on Shell's experimental data. E. POLICY IMPLICATIONS
1. General policies The policy implications relating to past and continued human exposure to Dieldrin were summarized in my cancellation testimony as follows: 212
"There is a growing and now general recognition that the majority of human cancers are due to environmental chemical carcinogens and that they are hence preventable. All chemicals, with the possible exception of trivalent arsenic, which are carcinogenic in humans, also produce cancers in experimental animals. Additionally, there is a close degree of parallelism between the characteristics of the wide range of cancers seen in humans and animals. There is no basis for the concept of 'species-specific' carcinogens. Furthermore, there is no basis for attempted differentiation, from either scientific or regulatory standpoints, of carcinogenicity data derived from the mouse in general, and from liver cancer in mice, in particular, from such data in any other species including m a n . " (EDF Ex. 33, p. 105). "The economic impact of cancer is massive. The direct costs of hospitalization and medical care for cancer in 1969 exceeded $500 million. The direct and indirect costs of cancer, including loss o f earnings during illness and during the balance of normal life expectancy, were estimated at a total of $15 billion for 1971; on the basis of analyses of selected cases, it appears that the total direct costs for a particular patient may range from $ 5,000 to over $20,000." ( E D F Ex. 33, p. 6).
2. Carcinogenicity of Dieldrin E v i d e n c e f o r t h i s h a s b e e n r e c e n t l y s u m m a r i z e d b y m e as f o l l o w s ( E D F Ex. 33, pp. 105-106): " T h e carcinogenicity of Dieldrin has been unequivocally demonstrated in valid independent studies in several strains of mice; while these data largely relate to hepatocarcinogenicity, other target organs are also clearly involved. Dieldrin is carcinogenic at the lowest dose, 0.1 ppm, yet tested in conventional systems. Additionally, more limited studies clearly indi. cate that Dieldrin is carcinogenic in the rat, in which the induction of liver cancers and o multiple site tumors has been demonstrated in one study. The other studies in rats and in dogs and monkeys are inadequate for the development of valid inferences on carcinogenicity. Even if there did exist negative evidence from valid well designed experiments (which is not the case), it would be properly superceded by the unquestionably valid positive results discussed herein. Finally, similar conclusions have been reached by independent epidemiologic experts on the results of the limited study of occupationally exposed adult males to Dieldrin and to related a n d unrelated pesticides. These experts are unanimous in their views that the data from this observation are quite inadequate for the development of valid inferences as to the noncarcinogenicity of Dieldrin. "These data overwhelmingly demonstrate that Dieldrin is an unequivocal carcinogen. Its continued use thus presents a serious potential carcinogenic hazard to man. The significance of these considerations is further emphasized by the extensive environmental contamination of Dieldrin, by the stability of Dieldrin and by the involuntary nature of general h u m a n exposure. Prudent public health policy thus demands immediate cessation of further uses of Dieldrin."
3. Involuntary nature of human exposure "Continuing h u m a n exposure to Dieldrin, in food, besides in water, is involuntary and generally occurs in the absence of knowledge and consent, not only as to the degree of exposure and its attendant potential hazards to large populations, but also as to the nature of the benefits, alleged or real, to the user besides society-at-large, apart from obvious benefits to the pesticide producer... It seems reasonable that continued use of Dieldrin, inter alia, should only be possibly justified if conscious societal decisions are made that the societal benefits o f its use outweigh its potential public health hazards, and if the existence of alternatives, which are similarly efficacious but less hazardous, has been critically excluded." ( E D F Ex. 33, p. 98).
4. "Safe" levels for carcinogens cannot be determined "There is no basis for the recognition of 'safe' levels of carcinogens in human populations. This dictum has been repeatedly stated and endorsed by a wide range of qualified expert 213
national and international committees and is unequivocally recognized by the 1958 Delaney Amendment to the Federal Food, Drug and Cosmetic Act (P.L.85-929), with relation to deliberate food additives." (EDF Ex. 33, p. 105). The latter conclusion has just been reiterated as follows in a letter dated 6/18/74 from H E W Secretary Weinberger to Congressman Staggers: "At present, the Department of Health, Education, and Welfare lacks the scientific information necessary to establish no-effect levels for carcinogenic substances in animals in general and in man in particular. In the absence of such information, we do not believe that detectable residues of carcinogenic animal drugs should be allowed in the food supply." This letter is attached hereto as Appendix A. Scientifically, no valid distinctions can be made between hazards f r o m carcinogenic residues of deliberate food additives and of accidental food additives, such as pesticides. These concepts have been emphasized by an expert A d Hoc C o m m i t t e e Report to the Surgeon-General, 1970, which stated: "The principle of a zero tolerance for carcinogenic exposure should be retained in all areas of legislation presently covered by it and should be extended to cover other exposures as well. Only... where contamination of an environmental source by a carcinogen has been proven to be unavoidable should exception be made," and then 'only after the most extraordinary justification is presented... Periodic review.., should be mandatory." (Ad Hoc Committee Report to Surgeon-General, 1970). As recently pointed out (Epstein, 1973), no such instances of " e x t r a o r d i n a r y justification" have yet been presented or documented, nor has the scientific case for "extraordinary justification" been made for continued exposure of h u m a n populations to Dieldrin residues in food and elsewhere in the environment. F. CONCLUSIONS (i) Any, agent which is conclusively shown to increase the incidence or shorten the latency of tumor induction in man or animals is a carcinogen by all recognized and standard definitions. There is no precedent or scientific basis for the alleged distinction between carcinogens and "augmenting agents." Indeed, such a distinction would define away the field of chemical carcinogenesis. N o r is there any justification for demanding information on basic mechanisms of action before classifying a chemical as carcinogenic. 0i) The variability in the spontaneous incidence o f liver tumors in mice provides no obstacle whatsoever to the demonstration of Dieldrin-induced carcinogenicity in the liver or in any other organ. (iii) Dieldrin has not been tested for carcinogenicity in infant animals. It is known that, in general, infant animals are more susceptible to chemical carcinogens than adults. The relatively high exposure of h u m a n infants to Dieldrin is thus cause for concern. (iv) Mice exposed to Dieldrin for limited periods early in life develop liver cancer late in life; the incidence of tumors is dependent on the period o f early exposure. Extrapolating these results to man, indicates that any prolongation of current exposure increases the degree of carcinogenic hazard. 214
(v) Exposure to Dieldrin is involuntary. (vi) There are thus cogent scientific grounds to demonstrate that continued exposure of human populations to Dieldrin constitutes an "imminent hazard". REFERENCES Ad Hoc Committee Report on the Evaluation of Low Levels of Environmental Carcinogens, Report to the Surgeon General, April 22, 1970. Della Porta, G., Food Cosmet. ToxicoL, 6 (1968) 243. Epstein, S. S., et al., Nature, 212 (1966) 1305. Epstein, S. S., et aL, Toxicol. AppL PharmacoL, 16 (1970) 432. Epstein, S. S., Preventive Med., 3 (1973) 140. Fiore-Donati, L., et aL, Nature, 190 (1961) 278. Flaks, A., Brit. J. Cancer, 20 (1966) 145. Health and Welfare, Canada, Testing of Chemicals for Carcinogenicity, Mutagenicity and Teratogenicity, September, 1973. IARC, Monographs o n the Evaluation of Carcinogenic Risk of Chemicals to Man, World Health Organization, International Agency for Research on Cancer, Lyon, Vols. I--6, 1972-1974. IARC Internal Technical Report No. 74]005 Report of a Working Committee on Vinyl Chloride, Lyon, France, 1974a. Liebelt, R., et al., Proc. Am. Ass. Cancer Res., 3 (1961) 245. O'Gara, R. W. and M. G. Kelly, Proc. Am. Ass. Cancer Res., 4 (1963) 49. Roe, F. J. C., et al., Brit. J. Cancer, 15 (1961) 515. Schmidt, A. (Commissioner, FDA), Hearings Before a Subcommittee of the Committee on Appropriations, House of Representatives, 93rd Congress, 1974, p. 17, Part. 8: Food and Drug Administration, Study of the Delaney Clause and other Anti-Cancer Clauses. Thorpe, E. and A. I. T. Walker, Fd. Cosmet. Toxicol., 11 (1973) 433. Thorpe, E., Shell Exhibit S. 5F, 1974. Toth, B., et al., Cancer Res., 24 (1964) 1712. Vesselinovitch, S., et aL, Cancer Res., 32 (1972) 2289. Walker, A. I. T., et al., Fd. Cosmet. ToxicoL, 11 (1973)415.
Note added in proof As a result o f the Suspension Hearings, EPA suspended future production, sale, and use of Aldrin and Dieldrin in October, 1974. The manufacturers appealed this decision, which was however upheld in the U.S. Courts of Appeal in the District of Columbia Circuit on April 4, 1975. APPENDIX
Department of Health, Education, and Welfare June 18th, 1974 Honorable Harley O. Staggers Chairman, Committee on Interstate and Foreign Commerce, House of Representatives, Washington, D.C. 20515 (U.S.A.) Dear Mr. Chairman: This is in response to your request for reports on H.R. 922 and H.R. 1171, bills "To amend the Federal Food, Drug, and Cosmetic Act to revise certain requirements for approval o f new animal drugs." 215
H.R. 922 and H. R. 1171 would amend the anticancer clause in section 512(d) (1) (H) of the Federal Food, Drug, and Cosmetic Act, which deals with new animal drugs and medicated feeds. Similar clauses exist in the food additives and color additives sections of the law but these would not be amended by either bill. All three clauses prohibit the approval of any food additive which causes cancer in man or other animal, except that, under an amendment to the Act by the Drug Amendments of 1962, an exception is provided in the case of carcinogenic ingredients in animal feeds if the animal is not harmed and if no residues of the drug may be detected by prescribed or approved methods in edible portions of the animals. Both H.R. 922 and H. R. 1171 would expand this exception by providing additional circumstances under which use of carcinogenic animal drugs in food animals may be allowed. The effect of H.R. 922 is to allow residues of such drugs in food for human consumption if they are not "cancer inducing". Similarly, H.R. 1171 would permit such residues if it has been shown, by scientific tests considered appropriate by the Secretary, that the amount or form of such residues will not induce cancer in humans. At present, the Department of Health, Education, and Welfare lacks the scientific information necessary to establish no-effect levels for carcinogenic substances in animals in general and in man in particular. In the absence of such information, we do not believe that detectable residues of carcinogenic animal drugs should be allowed in the food supply. The department has encouraged qualified scientific agencies and organizations to undertake comprehensive studies and analyses of the several anticaneer clauses of the Act. In addition, the Department itself has devoted considerable effort to expand current knowledge in this area. One such effort is our National Center for Toxicological Research (NCTR), which will assist in development of scientific data to support an accurate determination of the degree of risk to an animal population from long-term, low-dosage exposure to various substances, and may eventually enable us with confidence to extrapolate that risk to human experience. The NCTR program is designed to increase our knowledge through the orderly establishment of appropriate experimental designs and toxicological tests, statistical methods for comparison of lower doses to those practical in safety evaluation, and experimentation in comparative pharmacology, metabolism, and pathology which will support the appropriateness of extrapolation. The Department is also the leader in a major national effort to discover the fundamental mechanisms of carcinogenesis. Through these efforts, it may someday be possible for the Department to establish levels at which residues of carcinogens can safely be tolerated in human food without risk of cancer to humans. Until the necessary scientific data base exists to establish such levels, however, we oppose enactment of legislation such as H.R. 922 or H.R. 1171 to amend or even repeal one or all of the anticaneer clauses of the Act. Enactment of such legislation would have no effect on current Department policies since, under the present state of scientific knowledge, the general safety provisions of the Act would not permit this Department to allow detectable residues of carcinogenic animal drugs in human food. 216
The Department has supported wide public discussion of the benefit-risk issues involved in the anticancer clauses of the Act so that societal judgments and values can be incorporated into the regulatory mechanism by which it is decided which chemicals will be allowed in food. Difficult decisions are quite likely to confront us in the future since new agricultural and food manufacturing practices, many involving new chemical entities, will increasingly be relied upon to achieve expanded food production. It is conceivable that it may someday be necessary to abandon current policies reflected in the anticancer clauses in favor of an alternative accommodation between benefit and risk. Although we do not believe that the antieancer clauses--or the Department's policy under the general safety provisions of the Act-have had any deleterious effect on the food supply, the day may come when the knowledge base may be available so that the Congress will be in a position to permit exceptions from present law for additives which may be carcinogenic but are found to be of great importance to the food supply. The Department therefore recommends against enactment of H.R. 922 and H.R. 1171 since enactment of legislation to amend the anticancer clauses is premature considering the present state of scientific knowledge and the lack of public consensus as to the wisdom of changing current policies concerning carcinogens in food. We are advised by the Office of Management and Budget that there is no objection to the presentation of this report from the standpoint of the Administration's program. Sincerely, /s/Caspar W. Weinberger Secretary
Editorial Note Sufficient evidence is now available (if often only circumstantial) relating the incidence of various types of cancer with products of man's cultural state of advancement. Thus Carcinogenicity of Dieldrin, Part 1, by S. S. Epstein presented a comprehensive review of the carcinogenic nature of one chemical, viz., Dieldrin; the author concluded that this compound should no longer be used. In order to illustrate a practical result of scientific investigation and deliberation to reduce some risks to the health of man. Part//reproduces the Testimony of the U.S. Suspension Hearings (1974) together with relevant correspondence. As there is no basis for the recognition of "safe levels" of carcinogens in man and as the latent period for several forms of cancer in man may be at least 20 years, no effort should be spared in investigating those compounds which are or may be related to the induction and development of cancer. Animal experiments provide very valuable indications of possible carcinogens in man, but do not always cover a sufficient time span, neither can they reproduce the multifactorial nature of human exposure. E.I.H.
217
THE CARCINOGENICITY
OF DIELDRIN.
P A R T II*
SAMUEL S. EPSTEIN Medical School, Case Western Reserve University, Cleveland, Ohio (U.S.A.)
(Received February 27th, 1975)
A. CHARACTERIZATION OF CARCINOGENS 1. D e f i n i t i o n
Carcinogens h a v e been defined b y myself a n d o t h e r witnesses in the cancellation hearing ( E D F Ex. 33, p. 7; E P A Ex. 40, p. 4; E P A Ex. 46, pp. 4-5), as chemical, physical o r b i o l o g i c a l agents, e x p o s u r e o f animals o r h u m a n s to which increases the p r o b a b i l i t y o f i n d u c t i o n o f benign o r m a l i g n a n t t u m o r s (neoplasms). This m a y m a n i fest as follows: "Increase in the tumor incidence in a given population, i.e., an increase in the number of tumor-bearing individuals. Increase in the number of tumors in each individual. Reduction in the latent period of tumor induction. Any combination of the above effects (EDF Ex. 33, p. 7)." The essential features o f this definition have been reiterated, as follows, b y each o f six successive expert c o m m i t t e e s o f the I n t e r n a t i o n a l Agency for Research in C a n c e r ( I A R C ) , in a series o f m o n o g r a p h s , published between 1972 a n d 1974, on the " E v a l u a t i o n o f C a r c i n o g e n i c Risks o f Chemicals to M a n " : "The response in experimental animals to a carcinogen may take several forms: (a) a significance increase in the incidence of one or more of the same types of neoplasms as found in control animals; (b) the occurrence of types of neoplasms not observed in control animals; (c) a decreased latent period as compared with control animals. "For present purposes, in general, no distinction is made between the induction of tumors and the enhancement of tumor incidence, although it is noted that there may be fundamental differences in mechanisms that will eventually be elucidated (IARC, 1974)." This s t a n d a r d definition o f c h e m i c a l carcinogens is p r a g m a t i c a n d depends on the r e c o g n i t i o n o f a n association between cause (or stimulus) and effect (or response). In no w a y is this definition influenced by the presence or absence o f i n f o r m a tion on the u n d e r l y i n g basic m e c h a n i s m s involved or b y the frequency o f occurrence o f s p o n t a n e o u s t u m o r s in u n e x p o s e d o r c o n t r o l animals o r humans. * Statement o f Testimony at Suspension Hearings on Aldrin/Dieldrin (Environmental Protection Agency and Environmental Defense Fund vs. Shell), September 1974. Part I appeared in Sci. Total Environ., 4 (1975) 1. Both statements were made by the author as witness to and consultant
for EPA and EDF. 205
2. On the alleged distinction between carcinogenic and "augmenting'" or "enhancing" or modifying" effects of Dieldrin a. Semantic nature of alleged distinctions Several of Shell's employee witnesses have stated that the induction o f an increased number of tumors in Dieldrin-treated mice is not sufficient to characterize Dieldrin as a carcinogen. This mythology implies what is essentially a new and highly restrictive concept of chemical carcinogens. Dr. Thorpe, for example ( E P A 42J, p. 440) invokes the concept of "the unknown oncogenic stimulus", supposed to be present in mice, and responsible for the observed incidence of " s p o n t a n e o u s " tumors, i.e., tumors in control or untreated mice. In his statement (p. 45), Dr. Thorpe maintained that compounds, such as Dieldrin and phenobarbital, may increase tumor incidence by "enhancing or augmenting an existing oncogenic stimulus" (author's emphasis). Dr. Thorpe further stated that "Empirical extrapolation (sic) of this phenomenon to other mammals is not tenable since there are no data to indicate that the causal agent of liver tumors in mice operates in other species." Dr. Wright (Statement, p. 26-27) similarly maintains, "Since tumors were observed in control mice, an oncogenic stimulus was present in these animals." Dr. Wright concludes from this (Statement, p. 27) that "faced with an increased incidence of 'control' tumors, current techniques and current understanding do not allow us to discriminate between an augmenting (co-carcinogenic) effect or a carcinogenic effect by Dieldrin or phenobarbitone... In my view, (this) factor is the most relevant to current issues..." The notion that a hypothetical "pre-existing oncogenic stimulus" must be excluded before a chemical can be considered carcinogenic is at variance with established definitions of chemical carcinogens (vide supra). Since in most cases it is impossible to rule out the existence of such an unknown factor, acceptance of the Shell position would consign most chemicals now classified as carcinogens to an indeterminate area--neither carcinogens nor non-carcinogens. Indeed, by contrived semantics, this might succeed in defining away the entire problem of chemical carcinogenesis. The inappropriateness of such a restrictive definition has been recently stressed b y Dr. Heston: "A carcinogen, therefore, should not be defined only as something that produces tumors in a strain in which tumors never occur without the carcinogen. Such a strain probably does not exist" (EPA Ex. 46, p. 5).
b. Dependence of the "Augmenting Factor" proposition on sample size T h e alleged distinction between carcinogens and "augmenting factors" hinges on the possibility of determining whether or not a certain type of tumor does occur " s p o n t a n e o u s l y " or not in the observed animal or human population. This possibility depends largely on the size of the population sample that can be examined. F o r cer206
tain rare human cancers, populations exceeding I0 million would have to be surveyed before a single instance could be identified. Illustratively, the approximate "spontaneous" incidence of angiosarcoma of the liver is 0.014 cases per million annually (IARC, 1974a), and is thus considered by the IARC committee to be a carcinogen. By Shell's definition, however, once the extremely rare, but nevertheless finite, background incidence of angiosarcomas was recognized, vinyl chloride would presumably be relegated to the category of an "augmenting agent." A less extreme example would be the observed effects of cigarette smoking, which, in the last few decades, has massively increased the incidence of a higher to comparatively low incidence of lung cancer. Cigarette smoke would presumably not be regarded as carcinogenic by the Shell employee witnesses, as "spontaneous" lung cancer does occur in non-smokers. c. On the alleged necessity for information on underlying mechanisms in ascribing the property of carcinogenicity to an agent Dr. Stevenson (Statement, p. 17) said that the association of Dieldrin with increased incidence of tumors in mice may simply reflect a "modifying effect" on the background incidence of tumors, and that elucidation of the underlying carcinogenic mechanism would be necessary before extrapolating this result toward the human situation. In cross-examination (STR-537), Dr. Stevenson admitted that Dieldrin feeding was associated with an increase in liver tumor incidence; five strains (CFI, C3H, Swiss-Webster, LACG, and the CF1 X LACG hybrid), but then continued,
"I am not prepared to say that this indicatesthat... Dieldrin is a carcinogen,per se, until I have further information indicatingthat there is a causal relationship." The basis for this question of mechanisms appears to be the well recognized fact that a wide range of environmental factors, or "biases", such as position in the animal room, cage type, diet and hormonal status can significantly influence the pattern of "spontaneous" tumors in untreated laboratory animal populations. The purpose of utilizing control animals in scientific experiments is precisely to eliminate or minimize all such environmental effects. The only effects difficult to control are those directly related to the experimental variable, e.g., a compound in the diet could affect total dietary intake, which has been shown to affect tumor frequencies. In this regard, I note that the Shell employee witness with overall scientific responsibility for the toxicology programs in Shell's Tunstall Laboratories, Dr. Stevenson, stated that they had tried to eliminate "biases" as much as possible in the various mouse tests on the carcinogenicity of Dieldrin, and admitted that he was unable to specify any other "biases". (STR.-465). The emphasis by Shell witnesses that knowledge of mechanisms must be defined before any agent can be considered carcinogenic, even though this agent has been demonstrated to induce carcinogenic effects in valid experimental systems, can only be regarded as misleading in extreme. In fact, in spite of a very considerable amount of research, the basic mechanisms of action of any single carcinogen have not yet been elucidated. This requirement of Shell would define away the entire field of chemical carcinogenesis. 207
3. On alleged distinctions between tumorigens and carcinogens Numerous expert individuals and national and international committees have unequivocally emphasized the invalidity of alleged distinctions between "tumorigens" and carcinogens and have emphasized that these terms are virtually synonymous (EDF, Ex. 33, pp. 28-31; EPA Ex. 40B, p. 12; EPA Ex. 40C, p. 16; EPA Ex. 40H, p. 2). One Shell witness, Dr. Coulston, has made the unsubstantiated allegation that this principle is obsolete and no longer accepted by cancer experts (STR.-1807). However, these concepts have been consistently reiterated by six recent IARC expert committees on chemical carcinogens. An IARC report published this year, states: "The qualitative nature of neoplasia has been much discussed. In many instances both benign and malignant tumors are induced by chemical carcinogens. There are so far few recorded instances in which only benign tumors are induced by chemicals that have been studied extensively.Their occurrence in experimental systems has been taken to indicate the possibility of an increased risk of malignant tumors also" (IARC, 1974). This consensus is in striking contrast with the statements of some Shell witnesses (STR-1430, 1480, 1482, 1542) who have attempted to develop poorly substantiated distinctions between carcinogens and tumorigens, the latter being alleged to be of less significance with regard to presumptive human cancer risk. However, this point is apparently not in serious contention, as Shell's principal current pathologist has explicitly rejected the tumorigen concept (Dr. Thorpe, Shell Ex. S-5, p. 23, and STR-1042). B. ON THE ALLEGED HIGH AND VARIABLE SPONTANEOUS TUMOR FREQUENCIES IN THE MOUSE LIVER At least two Shell witnesses have discounted the significance of the Dieldrininduced carcinogenicity data in the mouse on the alleged basis that the spontaneous appearance of hepatic tumors in the mouse is too high and/or too variable from strain to strain or, within the same strain, but on different occasions, for meaningful study (STR.-1248, 1249; Shell S 1, pp. 41-42). T o examine this contention, I have compiled a table on the incidence o f liver tumors in both Dieldrin-treated and control groups of CF1 mice, as reported in the various Tunstall Studies (Table 1). F r o m consideration of the frequencies of malignant hepatic neoplasms, as diagnosed by Shell's pathologists (type " b " tumors), it is apparent that their spontaneous incidence in control animals, particularly in the females, is neither high n o r variable, while the Dieldrin-treated groups consistently show marked and often high incidences of such malignancies. The association of "type b " neoplasms with Dieldrin feeding has never been of serious contention in these hearings. The frequencies of the "type a " tumors are more variable, as in fact would be expected. " T y p e a " is a Shell-suggested classification which presumably covers a wide range of histopathological conditions, including hyperplasia, pre-neoplastic lesions and liver nodules, the incidence of which is probably age-dependent. While Shell's studies report the maximum duration of each experiment, lifespan sfor individual 208
TABLE 1 INCIDENCE OF HEPATIC TUMORS (10 ppm Dieldrin in the diet) M I C E Study
Walker, et al., 1973 expt. 1 expt. 2.1 expt. 2.2
unsterilized diet irradiated diet irrad, diet & bed. expt. 2.3
I N CF1 C O N T R O L
% o f males
% of females
Controls
Treated
C o n t r o l s Treated
a
b
a
b
a
b
a
b
16 12
4 0
37 36
57 9
13 10
0 0
37 41
55 12
30 20 42 13
4 3 0 0
58 40 63
25 20 23 not
23 11 17 17
0 0 0 0
36 32 42
23 11 21
6 52 25
0 0 5
applicable expt. 2.4 Thorpe & Walker, 1973 Thorpe, 1974
AND TREATED
11 44 4
0 9 2
46 47 13
54 53 40
not applicable 66 40 7
22 47 66
animals are not specified on an actuarial basis. It is clear that both control and treated mice were dying throughout the experiments, especially in the period after 12 months, when new tumors progressively appear. In these circumstances, the number of tumors classified as "type a" at the time of death will depend critically on the lifespan of the animals, besides on other aspects of the experimental design. Under such conditions, it is likely that the frequencies of "type a" tumors will vary from experiment to experiment, unless comparisons are made on an age-adjusted basis. Despite this variability, Table 1 indicates that the frequency of "type a" tumors is clearly enhanced by Dieldrin treatment. The sole exception is among the females of the 1973 Thorpe and Walker study, in which "type b" tumors were increased from 0 to 47% by Dieldrin treatment. This left relatively few treated animals in which "type a" tumors could occur. The very purpose of controlled experiments, performed with adequate numbers of animals, as in Shell's Tunstall Studies, is to overcome natural biological variability and demonstrate effects, or their absence. Shell's own experiments clearly demonstrate how natural variability can be surmounted and an unequivocal result be obtained. The alleged high variability in the incidence of liver tumors in control mice has been used by Shell witnesses to challenge the role of mice in carcinogenicity testing. There are numerous statements in the literature, from a wide range of individual experts and expert national and international committees, substantiating the critical value of mice for carcinogenicity testing and for development of data which can be extrapolated to man (EDF Ex. 33, pp. 21-25). In this connection it is also important to note that the mouse is the standard reference test animal in recently established 209
and large scale H E W programs at the National Center for Toxicological Research, Pine Bluff, Ark., for quantitation of toxicologic and carcinogenic risk. Confidence in the mouse model for this purpose has been deafly stated by senior H E W spokesmen at recent Congressional hearings, illustratively, as follows (Schmidt, 1974): "The first large scale chronic study involving approximately 25,000 mice that was initiated on April 15 is not designed to find a threshold level of the carcinogen, 2-AAF. Rather, this experiment with over 700 different treatment groups is structured to produce experimental data that can be used for the development of improved mathematical models for quantitation of toxicologic and carcinogenic risk. Also, this experiment will provide reference data on chronic toxicity against which results attained using other testing methodologies can be compared." C. ON THE SUSCEPTIBILITY OF INFANTS TO CARCINOGENS It has been claimed, chiefly by Dr. van Raalte, that h u m a n babies are at no greater or even less risk to Dieldrin carcinogenesis than the general population, although their intake, on a body weight basis is greater than in adults ( B o m k a m p , EPA Ex. 38). Dr. van Raalte dismisses the fact that breast-fed babies in the first three months of life accumulate more Dieldrin on a b o d y weight basis, t h a n any other age group by saying, "the three-month period about which concern was expressed is only 1/284 or 0.35% of a lifetime." (My emphasis). H e further states that in babies, Dieldrin is "promptly stored.., in the lipid tissue.., and thus do(es) not give rise to an increasing concentration in the target tissues." Dr. van Raalte concludes that: "The question of whether the presently possible level of intake of Dieldrin by breast-fed babies is safe can.., only be answered in the affirmative" (Statement, pp. 54-58). This judgment appears both uninformed and irresponsible. N e w b o r n animals have been repeatedly demonstrated to be more sensitive to carcinogenic effects than adults. F o r these reasons, it has been widely recommended, including elsewhere, by a Shell witness, Dr. F. J. C. Roe (Roe et al., !961), that infant animals should be used in screening for chemical carcinogens (Della Porta, 1968; Epstein, et al., 1970; Health and Welfare, Canada, 1973). The following examples illustrate this enhanced sensitivity: (i) Aflatoxin B1 has not been shown carcinogenic in adult mice. However, when injected into 1-day-old animals of the same strain, h e p a t o m a s were induced by 52 weeks (Vesselixovitch et al., 1972). (ii) 3-Methylcholanthrene-induced lung tumors appeared 24 weeks following its injection in 2-week old mice. Such mice had six times the n u m b e r of tumors found in animals injected at 4 weeks, and 21 times the n u m b e r o f tumors in mice injected at 8 weeks of age ( O ' G a r a and Kelly, 1963). (iii) Urethane, a well-studied mouse carcinogen, has been shown to be m o r e carcinogenic when administered to newborn than adult mice (Liebelt et al., 1961). 210
In another study, urethane injected into newborn mice induced leukemia, while no comparable results were obtained with adult mice (Fiore-Donati et al., 1962). (iv) Dimethylnitrosamine, injected on a single occasion was found to be highly hepatocarcinogenic in mice, provided it was administered before the animals were 24 hours old. On the other hand, administration of the compound for 141 consecutive days, commencing at age of 5 weeks, failed to induce hepatic tumors (Toth et al., 1964). (v) Condensed cigarette smoke induced lung adenomas after a single injection in mice aged less than 12 hours (47% of the animals showed lung adenomas after 1 year). If injected at age 7 days, 40% of the animals showed lung adenomas after one year, while if injected at 14 days, only 20% of the animals showed the tumors after one year. Control animals had a lung adenoma rate of 1.5% (Flaks, 1966). (vi) Organic extracts of particulate atmospheric pollutants collected from various cities in the U.S.A. induced, in varying incidence, pulmonary adenomas, hepatomas and lymphomas following administration to infant mice (Epstein et al., 1966). With the exception of pulmonary adenomas, these tumors have not been reported following administration of extracts to mature mice. Dieldrin carcinogenicity has never been studied in neonatal animals. Dr. van Raalte's statement that Dieldrin is "promptly" stored in the fat of the "rapidly growinginfant.., and thus does not give rise to an increasingconcentrationin the target tissues" provides no evidence that infants would be any less susceptible to Dieldrin carcinogenicity than adults. Indeed, the converse seems more likely. In this connection, it is of interest to note that much experimental data, including some cited above, indicating the enhanced sensitivity to carcinogenicity relates to lipid-soluble carcinogens, which like Dieldrin tend to be selectively stored in body fat. There is no evidence whatsoever that such storage sequesters carcinogens and hence protects against chemical carcinogenesis. D. DIELDRIN AS AN IMMINENT HAZARD The issue in these suspension proceedings is whether the projected 1975 uses of Alddn/Dieldrin present an "imminent hazard" which would require immediate suspension of its major uses prior to the conclusion of the cancellation proceedings. The question thus posed is whether use of Dieldrin for one more year, 1975, would significantly increase carcinogenic hazards to man posed by existing environmental and body burdens. It has been estimated that the total sales of Aldrin/Dieldrin over the last 25 years in the U.S.A. approximates to 250 million pounds (Shell Ex. 111, Table I 1); the projected use of an approximate additional 10 million pounds in 1975 would thus constitute an increment of approximately 4% of the total burden of Dieldrin already introduced into the environment. 211
Testimony at these hearings (Fisher, Testimony at Suspension Hearings), has demonstrated that, where comparisons can possibly be made, it can be seen that residues of Dieldrin in food have not significantly changed in recent years. Thus, if a similar quantity of Aldrin/Dieldrin were to be used for similar purposes in 1975 as that which has been used annually over the past several years, it would be reasonable to assume that there would probably be no change in dietary residue levels. Further usage of Dieldrin for an additional year, 1975, would postpone b y one year the anticipated onset of the overall decline in the environmental burden o f Dieldrin and the consequent decline in levels of human exposure. The relevance to m a n of such a prolongation of Dieldrin exposure is amply demonstrated by experimental evidence from Shell's studies in mice (Walker et al., 1973, Study 2.4). These studies clearly indicate a positive relation between duration of exposure of mice to Dieldrin and the incidence of liver tumors (Table 2). The carcinogenic effects of Dieldrin, besides being dose-dependent, are thus also clearly time-dependent. Assuming that TABLE 2 T I M E - D E P E N D E N C Y OF D I E L D R I N E X P O S U R E O N C A R C I N O G E N I C EFFECTS IN MICE Duration o f feeding (Weeks)
No. mice ( M & F) with liver tumors (A & B)/Nos. at risk
% Incidence-liver tumors
0 2 4 8 16 32 64
3/43 4/22 5/22 8/22 7/19 8/20 21/22
9 18 23 36 37 40 95
humans and mice are similarly sensitive to the carcinogenic effects of Dieldrin--and there is no way of determining whether humans are more or less sensitive--then this striking time-dependency would also be expressed in humans. Further, assuming a similar pattern of time-dependency, relating duration of Dieldrin exposure a n d tumor incidence, in man as has been experimentally demonstrated in mice, then it is clear that the continued use of Dieldrin for a further year, 1975, would increase the carcinogenic hazard to man. The factor by which this hazard would be increased is currently indeterminate, though it would appear to be high, based on Shell's experimental data. E. POLICY IMPLICATIONS
1. General policies The policy implications relating to past and continued human exposure to Dieldrin were summarized in my cancellation testimony as follows: 212
"There is a growing and now general recognition that the majority of human cancers are due to environmental chemical carcinogens and that they are hence preventable. All chemicals, with the possible exception of trivalent arsenic, which are carcinogenic in humans, also produce cancers in experimental animals. Additionally, there is a close degree of parallelism between the characteristics of the wide range of cancers seen in humans and animals. There is no basis for the concept of 'species-specific' carcinogens. Furthermore, there is no basis for attempted differentiation, from either scientific or regulatory standpoints, of carcinogenicity data derived from the mouse in general, and from liver cancer in mice, in particular, from such data in any other species including m a n . " (EDF Ex. 33, p. 105). "The economic impact of cancer is massive. The direct costs of hospitalization and medical care for cancer in 1969 exceeded $500 million. The direct and indirect costs of cancer, including loss o f earnings during illness and during the balance of normal life expectancy, were estimated at a total of $15 billion for 1971; on the basis of analyses of selected cases, it appears that the total direct costs for a particular patient may range from $ 5,000 to over $20,000." ( E D F Ex. 33, p. 6).
2. Carcinogenicity of Dieldrin E v i d e n c e f o r t h i s h a s b e e n r e c e n t l y s u m m a r i z e d b y m e as f o l l o w s ( E D F Ex. 33, pp. 105-106): " T h e carcinogenicity of Dieldrin has been unequivocally demonstrated in valid independent studies in several strains of mice; while these data largely relate to hepatocarcinogenicity, other target organs are also clearly involved. Dieldrin is carcinogenic at the lowest dose, 0.1 ppm, yet tested in conventional systems. Additionally, more limited studies clearly indi. cate that Dieldrin is carcinogenic in the rat, in which the induction of liver cancers and o multiple site tumors has been demonstrated in one study. The other studies in rats and in dogs and monkeys are inadequate for the development of valid inferences on carcinogenicity. Even if there did exist negative evidence from valid well designed experiments (which is not the case), it would be properly superceded by the unquestionably valid positive results discussed herein. Finally, similar conclusions have been reached by independent epidemiologic experts on the results of the limited study of occupationally exposed adult males to Dieldrin and to related a n d unrelated pesticides. These experts are unanimous in their views that the data from this observation are quite inadequate for the development of valid inferences as to the noncarcinogenicity of Dieldrin. "These data overwhelmingly demonstrate that Dieldrin is an unequivocal carcinogen. Its continued use thus presents a serious potential carcinogenic hazard to man. The significance of these considerations is further emphasized by the extensive environmental contamination of Dieldrin, by the stability of Dieldrin and by the involuntary nature of general h u m a n exposure. Prudent public health policy thus demands immediate cessation of further uses of Dieldrin."
3. Involuntary nature of human exposure "Continuing h u m a n exposure to Dieldrin, in food, besides in water, is involuntary and generally occurs in the absence of knowledge and consent, not only as to the degree of exposure and its attendant potential hazards to large populations, but also as to the nature of the benefits, alleged or real, to the user besides society-at-large, apart from obvious benefits to the pesticide producer... It seems reasonable that continued use of Dieldrin, inter alia, should only be possibly justified if conscious societal decisions are made that the societal benefits o f its use outweigh its potential public health hazards, and if the existence of alternatives, which are similarly efficacious but less hazardous, has been critically excluded." ( E D F Ex. 33, p. 98).
4. "Safe" levels for carcinogens cannot be determined "There is no basis for the recognition of 'safe' levels of carcinogens in human populations. This dictum has been repeatedly stated and endorsed by a wide range of qualified expert 213
national and international committees and is unequivocally recognized by the 1958 Delaney Amendment to the Federal Food, Drug and Cosmetic Act (P.L.85-929), with relation to deliberate food additives." (EDF Ex. 33, p. 105). The latter conclusion has just been reiterated as follows in a letter dated 6/18/74 from H E W Secretary Weinberger to Congressman Staggers: "At present, the Department of Health, Education, and Welfare lacks the scientific information necessary to establish no-effect levels for carcinogenic substances in animals in general and in man in particular. In the absence of such information, we do not believe that detectable residues of carcinogenic animal drugs should be allowed in the food supply." This letter is attached hereto as Appendix A. Scientifically, no valid distinctions can be made between hazards f r o m carcinogenic residues of deliberate food additives and of accidental food additives, such as pesticides. These concepts have been emphasized by an expert A d Hoc C o m m i t t e e Report to the Surgeon-General, 1970, which stated: "The principle of a zero tolerance for carcinogenic exposure should be retained in all areas of legislation presently covered by it and should be extended to cover other exposures as well. Only... where contamination of an environmental source by a carcinogen has been proven to be unavoidable should exception be made," and then 'only after the most extraordinary justification is presented... Periodic review.., should be mandatory." (Ad Hoc Committee Report to Surgeon-General, 1970). As recently pointed out (Epstein, 1973), no such instances of " e x t r a o r d i n a r y justification" have yet been presented or documented, nor has the scientific case for "extraordinary justification" been made for continued exposure of h u m a n populations to Dieldrin residues in food and elsewhere in the environment. F. CONCLUSIONS (i) Any, agent which is conclusively shown to increase the incidence or shorten the latency of tumor induction in man or animals is a carcinogen by all recognized and standard definitions. There is no precedent or scientific basis for the alleged distinction between carcinogens and "augmenting agents." Indeed, such a distinction would define away the field of chemical carcinogenesis. N o r is there any justification for demanding information on basic mechanisms of action before classifying a chemical as carcinogenic. 0i) The variability in the spontaneous incidence o f liver tumors in mice provides no obstacle whatsoever to the demonstration of Dieldrin-induced carcinogenicity in the liver or in any other organ. (iii) Dieldrin has not been tested for carcinogenicity in infant animals. It is known that, in general, infant animals are more susceptible to chemical carcinogens than adults. The relatively high exposure of h u m a n infants to Dieldrin is thus cause for concern. (iv) Mice exposed to Dieldrin for limited periods early in life develop liver cancer late in life; the incidence of tumors is dependent on the period o f early exposure. Extrapolating these results to man, indicates that any prolongation of current exposure increases the degree of carcinogenic hazard. 214
(v) Exposure to Dieldrin is involuntary. (vi) There are thus cogent scientific grounds to demonstrate that continued exposure of human populations to Dieldrin constitutes an "imminent hazard". REFERENCES Ad Hoc Committee Report on the Evaluation of Low Levels of Environmental Carcinogens, Report to the Surgeon General, April 22, 1970. Della Porta, G., Food Cosmet. ToxicoL, 6 (1968) 243. Epstein, S. S., et al., Nature, 212 (1966) 1305. Epstein, S. S., et aL, Toxicol. AppL PharmacoL, 16 (1970) 432. Epstein, S. S., Preventive Med., 3 (1973) 140. Fiore-Donati, L., et aL, Nature, 190 (1961) 278. Flaks, A., Brit. J. Cancer, 20 (1966) 145. Health and Welfare, Canada, Testing of Chemicals for Carcinogenicity, Mutagenicity and Teratogenicity, September, 1973. IARC, Monographs o n the Evaluation of Carcinogenic Risk of Chemicals to Man, World Health Organization, International Agency for Research on Cancer, Lyon, Vols. I--6, 1972-1974. IARC Internal Technical Report No. 74]005 Report of a Working Committee on Vinyl Chloride, Lyon, France, 1974a. Liebelt, R., et al., Proc. Am. Ass. Cancer Res., 3 (1961) 245. O'Gara, R. W. and M. G. Kelly, Proc. Am. Ass. Cancer Res., 4 (1963) 49. Roe, F. J. C., et al., Brit. J. Cancer, 15 (1961) 515. Schmidt, A. (Commissioner, FDA), Hearings Before a Subcommittee of the Committee on Appropriations, House of Representatives, 93rd Congress, 1974, p. 17, Part. 8: Food and Drug Administration, Study of the Delaney Clause and other Anti-Cancer Clauses. Thorpe, E. and A. I. T. Walker, Fd. Cosmet. Toxicol., 11 (1973) 433. Thorpe, E., Shell Exhibit S. 5F, 1974. Toth, B., et al., Cancer Res., 24 (1964) 1712. Vesselinovitch, S., et aL, Cancer Res., 32 (1972) 2289. Walker, A. I. T., et al., Fd. Cosmet. ToxicoL, 11 (1973)415.
Note added in proof As a result o f the Suspension Hearings, EPA suspended future production, sale, and use of Aldrin and Dieldrin in October, 1974. The manufacturers appealed this decision, which was however upheld in the U.S. Courts of Appeal in the District of Columbia Circuit on April 4, 1975. APPENDIX
Department of Health, Education, and Welfare June 18th, 1974 Honorable Harley O. Staggers Chairman, Committee on Interstate and Foreign Commerce, House of Representatives, Washington, D.C. 20515 (U.S.A.) Dear Mr. Chairman: This is in response to your request for reports on H.R. 922 and H.R. 1171, bills "To amend the Federal Food, Drug, and Cosmetic Act to revise certain requirements for approval o f new animal drugs." 215
H.R. 922 and H. R. 1171 would amend the anticancer clause in section 512(d) (1) (H) of the Federal Food, Drug, and Cosmetic Act, which deals with new animal drugs and medicated feeds. Similar clauses exist in the food additives and color additives sections of the law but these would not be amended by either bill. All three clauses prohibit the approval of any food additive which causes cancer in man or other animal, except that, under an amendment to the Act by the Drug Amendments of 1962, an exception is provided in the case of carcinogenic ingredients in animal feeds if the animal is not harmed and if no residues of the drug may be detected by prescribed or approved methods in edible portions of the animals. Both H.R. 922 and H. R. 1171 would expand this exception by providing additional circumstances under which use of carcinogenic animal drugs in food animals may be allowed. The effect of H.R. 922 is to allow residues of such drugs in food for human consumption if they are not "cancer inducing". Similarly, H.R. 1171 would permit such residues if it has been shown, by scientific tests considered appropriate by the Secretary, that the amount or form of such residues will not induce cancer in humans. At present, the Department of Health, Education, and Welfare lacks the scientific information necessary to establish no-effect levels for carcinogenic substances in animals in general and in man in particular. In the absence of such information, we do not believe that detectable residues of carcinogenic animal drugs should be allowed in the food supply. The department has encouraged qualified scientific agencies and organizations to undertake comprehensive studies and analyses of the several anticaneer clauses of the Act. In addition, the Department itself has devoted considerable effort to expand current knowledge in this area. One such effort is our National Center for Toxicological Research (NCTR), which will assist in development of scientific data to support an accurate determination of the degree of risk to an animal population from long-term, low-dosage exposure to various substances, and may eventually enable us with confidence to extrapolate that risk to human experience. The NCTR program is designed to increase our knowledge through the orderly establishment of appropriate experimental designs and toxicological tests, statistical methods for comparison of lower doses to those practical in safety evaluation, and experimentation in comparative pharmacology, metabolism, and pathology which will support the appropriateness of extrapolation. The Department is also the leader in a major national effort to discover the fundamental mechanisms of carcinogenesis. Through these efforts, it may someday be possible for the Department to establish levels at which residues of carcinogens can safely be tolerated in human food without risk of cancer to humans. Until the necessary scientific data base exists to establish such levels, however, we oppose enactment of legislation such as H.R. 922 or H.R. 1171 to amend or even repeal one or all of the anticaneer clauses of the Act. Enactment of such legislation would have no effect on current Department policies since, under the present state of scientific knowledge, the general safety provisions of the Act would not permit this Department to allow detectable residues of carcinogenic animal drugs in human food. 216
The Department has supported wide public discussion of the benefit-risk issues involved in the anticancer clauses of the Act so that societal judgments and values can be incorporated into the regulatory mechanism by which it is decided which chemicals will be allowed in food. Difficult decisions are quite likely to confront us in the future since new agricultural and food manufacturing practices, many involving new chemical entities, will increasingly be relied upon to achieve expanded food production. It is conceivable that it may someday be necessary to abandon current policies reflected in the anticancer clauses in favor of an alternative accommodation between benefit and risk. Although we do not believe that the antieancer clauses--or the Department's policy under the general safety provisions of the Act-have had any deleterious effect on the food supply, the day may come when the knowledge base may be available so that the Congress will be in a position to permit exceptions from present law for additives which may be carcinogenic but are found to be of great importance to the food supply. The Department therefore recommends against enactment of H.R. 922 and H.R. 1171 since enactment of legislation to amend the anticancer clauses is premature considering the present state of scientific knowledge and the lack of public consensus as to the wisdom of changing current policies concerning carcinogens in food. We are advised by the Office of Management and Budget that there is no objection to the presentation of this report from the standpoint of the Administration's program. Sincerely, /s/Caspar W. Weinberger Secretary
Editorial Note Sufficient evidence is now available (if often only circumstantial) relating the incidence of various types of cancer with products of man's cultural state of advancement. Thus Carcinogenicity of Dieldrin, Part 1, by S. S. Epstein presented a comprehensive review of the carcinogenic nature of one chemical, viz., Dieldrin; the author concluded that this compound should no longer be used. In order to illustrate a practical result of scientific investigation and deliberation to reduce some risks to the health of man. Part//reproduces the Testimony of the U.S. Suspension Hearings (1974) together with relevant correspondence. As there is no basis for the recognition of "safe levels" of carcinogens in man and as the latent period for several forms of cancer in man may be at least 20 years, no effort should be spared in investigating those compounds which are or may be related to the induction and development of cancer. Animal experiments provide very valuable indications of possible carcinogens in man, but do not always cover a sufficient time span, neither can they reproduce the multifactorial nature of human exposure. E.I.H.
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