Exaggerated risks of chemicals

J Clin

Pergamon

08%-4356(94)00116-2

Vol. 48, No. 2. pp. 173-178, 1995 Copyright 1 1995 Elsevier Science Ltd Printed in Great Britain. All rights reserved 0895.4356/9S$9.50 + 0.00

Epidemiol

Commentary EXAGGERATED PHILIP American Association

RISKS OF CHEMICALS H. ABELSON

for the Advancement

of Science, Washington,

(Received ,for publication

The citizens of the United States have unreasonably great fears of chemicals. The Environmental Protection Agency (EPA) has become one of the most powerful governmental divisions in Washington. It has been given legal authority to create and enforce thousands of regulations. The impact of these regulations on all of us is in process of being increased. Tougher federal environmental enforcement will adversely affect taxpayers, agriculture, the chemical industry and the profession of chemistry. Until recently, the effects of regulatory zeal were not visible, though hundreds of billions of dollars have already been spent without provable benefits to the nation’s health. Currently there exists considerable public and special interest pressure to force reduction in the use of pesticides. There is no solid evidence that the tiny amounts remaining on fruits and vegetables are harmful. For many years the EPA has maintained regulatory levels so that an individual eating food containing the EPA top level of a pesticide for a lifetime would have less than one chance in a million of incurring cancer as a result of eating that food. Levels of pesticides in foods are monitored by the Food and Drug Administration. FDA findings indicate that only tiny concentrations of agricultural pesticides are present in foods in supermarkets and that a large fraction has no detectable amounts of pesticides at all [l]. In summary, pesticides in foods are having no more than a trivial effect if any on human health. In contrast, consuming substantial amounts of fruits and vegetables have long been sus-

DC, U.S.A.

5 July 1994)

pected to have beneficial effects. Many isolated studies of the matter have been published. Professor Gladys Block and associates of the University of California at Berkeley have performed a public service by assembling results of 172 studies conducted in places around the world [2]. Their analysis compared cancer rates for a quartile of people consuming an average of O-l fruits and vegetables a day with a quartile eating &5. The contrast in relative risk of cancer in various organs of the body was impressive. For example, the beneficial effect of consuming adequate amounts of fruits and vegetables was a factor of 2.2 for lung, 2.5 for stomach, 2.8 for pancreas and 1.9 for colorectal sites. Those great benefits to health are in danger of being curtailed. EPA Administrator Carol Browner has announced a goal of decreasing use of pesticides by 70% during the next three years. If this policy is implemented, production of many fruits and vegetables would be adversely affected. In other words, were EPA to ban pesticides and cause fruits and vegetables to become expensive or unavailable, it could be responsible for causing annually tens of thousands of cancer deaths. Having been an agent in causing widespread fear of cancer, EPA must now deal with consequences of its earlier actions. The public anxiety about pesticides and other chemicals led to demands for safety from them. Earlier, Congress passed many different complex laws. In numerous instances, the wording of these laws is conflicting. The EPA must also deal with the Delaney clause, which was enacted before the 173

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creation of EPA. Unless Congress repeals the Delaney clause, important agricultural chemicals essential to the production of fruits and vegetables will be banned. Another major threat to the production of cancer-preventing foods is a law that requires retesting of pesticides that have a long history of successful use. A provision of the law is that commercial producers of the pesticides must pay for all the costs of retesting. The tests required are so complicated and so numerous that as much as 50 million dollars per pesticide is involved. To avoid spending that kind of money, many producers have stopped supplying agricultural chemicals [3]. The number of commercially available pesticides has dropped. When only one pesticide is available for a given fruit or vegetable, the probability is increased of biological pests becoming resistant to human control. I now comment on aspects of the roles of agricultural pesticides. U.S. farmers use approx. 800 million pounds of active pesticide ingredients per year. About 500 million pounds are herbicides administered to control weeds on about 95% of land devoted to field crops such as corn. Their use permits no-till agriculture that minimizes soil erosion. Herbicides are designed to interfere with the unique synthetic pathways that are employed by plants to make aromatic amino acids. The herbicides used have little effect on human metabolism. About 150 million pounds of insecticides are used to control the more than 300 insect species that are injurious to crops grown in the United States. Some of the insects that infest major field crops can also be controlled by pheromones, but these substances are not generally available for the insects that attack fruits and vegetables. Many trees and plants are vulnerable to insects and to disease organisms that the insects carry. Were applications of insecticides to be curtailed, impacts on the availability of fruits and costs of fruits and vegetables would be great. About 65 million pounds of fungicides are used annually in the United States. They control many diseases. Under favorable conditions, fungi can destroy a healthy crop within a few days. All important plants are subject to attack by one or more species. Infection by fungi can cause great reductions in yield and quality. A study by GRC Economics estimates yield reductions if no fungicides are employed. The reductions were: for apples, 40%; for grapes, 33%; and for peaches, 49%.

Fungi cause deterioration of food crops both before and after harvest. Fungal infestation stimulates the defensive production by the target plants of toxic chemicals (some of which are carcinogens). Products of metabolism by the fungi include nerve, liver and kidney poisons and carcinogens. Among the fungal toxins are the aflatoxins, which are among the most potent carcinogens known. Were fungicides to be banned, damage to health from natural fungal products might well far exceed any presently caused by the commercial fungicides. The American Farm Bureau Research Foundation has released a study, “Economic Impacts of Reduced Pesticide Use on Fruits and Vegetables” [4]. An impressive number of university-based horticultural scientists and agricultural economists contributed. They analyzed effects of the banning of pesticides on nine major crops, including apples, grapes, lettuce, oranges, peaches and tomatoes. Depending on local conditions, in some instances 100% crop losses would occur. California agriculture would be greatly harmed. Costs of production would be substantially increased, inevitably leading to higher prices at supermarkets. Everyone would be affected, and especially those with low incomes. People deprived of fruits and vegetables have a substantially increased risk of cancer. Are the methods of risk assessment on which EPA bases its regulations valid? An increasing amount of evidence shows that EPA vastly exaggerates risks. I will next present some of that new evidence. Only a few industrially-produced chemicals are known to induce cancer in humans. In general, cancer is a disease of old age, and it is usually not manifested until long after initial exposures. In the 1970s fear of cancer led to a program of animal experimentation designed to detect possible carcinogens. The lifetimes of rats and mice are about two years, and in their metabolism they were thought to be good proxies for humans. Risk assessment procedures were established that continue to be employed. In an effort to achieve reproducibility, inbred rodents were used. The major strains of rodents employed 20 years ago are still being used. Fisher-344 rats have been inbred since 1920 [5] and now are the result of more than 100 generations of inbreeding. Other major strains of rodents employed in carcinogen testing also have lengthy histories of inbreeding. As might be expected, all the major strains have

Commentary

hereditary defects. Some show evidence of genetic drift. In the typical experiment, groupseach comprising 50 male and female rats and mice-are tested with accompanying controls. The experimental animals are kept in cages and are fed ad libitum. They tend to become obese. Experiments have shown that animals fed a complete but calorie-restricted diet are healthier, longer-lived, and about one-third as likely to die of cancer as are the obese animals. The effect of ad libitum feeding is to exaggerate the carcinogenicity of some substances by about a factor of 3. The test substances are administered to the rodents for most of their lives in three ways-in drinking water, food or by gavage. Following death, usually by sacrifice, tissues of the animals are examined and benign and malignant tumors are counted. The two sets of numbers are lumped together as being cancerous. Typically half the tumors are benign. The lumping of benign and malignant tumors exaggerates the carcinogenicity by a factor of 2. Usually all the groups of animals, including controls, are found to have developed tumors. Often some of the experimental groups have no more tumors than control groups. Those results are given little or no weight in risk assessments. Instead, the results from the most sensitive group of animals are deemed to be representative of effects on humans. Then to make an official risk assessment, arbitrary, unproven mathematical models are employed. These are deliberately designed to maximize the possible hazard for humans. Often the extrapolation from huge doses in the sensitive animals to tiny doses in humans involves a factor of a million or more. A substantial number of toxicologists at universities and in industry have published peerreviewed articles that criticize EPA procedures and interpretations [6]. Some toxicologists have stated that federal risk assessments exaggerate hazards by orders of magnitude. In what follows, the basic assumptions underlying EPA risk regulations are listed and samples of criticisms of them are provided. At least six basic arbitrary and unproven assumptions are involved in governmental risk assessment. In general, each exaggerates risks by large factors. Moreover, the exaggerations are to be multiplied. Thus the true risk is likely to be overstated by factors of 100 to infinity. I will deal with these six basic assumptions in turn.

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A first assumption is that: For purposes of cancer risk assessments, experiments on inbred, obese rodents provide a reliable basis for estimating carcinogenic effects of chemicals on humans. The rodents employed in risk assessments are inbred strains of rats or mice. Biologically, these test animals are more biologically uniform than are wild types. But inbreeding leads to hereditary weaknesses, as has also been noted in humans. The two principal strains of rats used in risk assessments have genetic defects. More than half of male F-344 rats develop leukemia by the age of 24 months. At that age, they all also suffer severe kidney disease. Nearly 100% of Sprague-Dawley female rats spontaneously develop pituitary tumors, and about half of them have mammary tumors. The most frequently used rodent is the B,C,F, mouse. This strain is more prone to developing spontaneous tumors than most other mice. The male B,C, F, mouse is especially likely to suffer spontaneous liver cancer [7]. In humans, absent chronic alcoholism or viral disease, liver cancer is rare. Nevertheless, solely on the basis of excess tumors in male B,C,F, mice, a substantial number of substances have been declared carcinogens. In summary: Dependence on experiments employing the usual inbred rats or B,C3F, mice that have high rates of spontaneous neoplasms is questionable. It is like conducting analytical chemistry in dirty test tubes. A second assumption is that: Results obtained from administration of huge, often toxic, maximum tolerated doses (MTDs) to rodents are relevant to calculating efects of tiny doses in humans. The administration of huge, nearly lethal MTDs of a test chemical is in reality merely a test to determine if massive doses can cause cancer. In about 60% of such tests, cancer is induced in rodents. The massive doses frequently result in cellular death, accompanied by cellular proliferation, which itself often leads to cancer. Effects of the use of huge doses in risk assessments prove once again what Paracelsus, a Swiss physician, knew 400 years ago: The dose makes the poison. There are many examples of substances essential to life that are lethal if administered in large amounts. Vitamin A is

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toxic if given in doses only IO-fold greater than the daily requirement. Methyl alcohol, also known as wood alcohol, causes blindness when ingested as an intoxicant. But methyl alcohol is a natural component of our metabolism and always is present in blood. Another example is formaldehyde, also a natural component of blood. At large concentrations in air it causes nasal cancer in rats. Even water can be lethal. Ordinary table salt in high dosage is a carcinogen, as is the essential element selenium. A third assumption is that: The efSect of a given dose of a chemical is independent of its rate and mode of administration. This assumption was used to justify extensive use of gavage as a mode of administration of chemicals. In the official National Toxicology Program reports [8] issued for 1980-1992, gavage was the method most often employed. Gavage was used to determine carcinogenicity of chloroform, an important minor constituent of drinking water. The chloroform was diluted in corn oil. Five days each week during a rodent’s lifetime a tube was passed through the mouth and esophagus into the stomach. Then corn oil containing a dose of chloroform was shot in. A consequence of the gavage treatment was that the rodents received a relatively sudden slug of chloroform. Excess liver cancer followed. Recently new experiments have been performed, comparing effects of administration of chloroform by gavage with effects of incorporating doses in drinking water [9]. The tests confirmed earlier experiments that had shown substantial differences in outcomes of the two different modes of administration. The new research explored mechanisms that led to liver tumors in gavage-treated animals. Development of liver tumors in these rodents was preceded by cytolethality and cell proliferation. Even with exposures of nearly 2 million parts per billion there was no induction of regenerative cell proliferation in the livers of animals receiving chloroform in drinking water. Others have criticized the sudden administration of corn oil on the grounds that the amounts involved disturb the normal metabolism of the rodents [lo]. I have been told that the use of gavage in the National Toxicology Program has been abandoned. However, regulations based on the results of gavage experiments have not been changed. EPA rarely admits or corrects its mistakes.

A fourth assumption is that: Humans and rodents do not d@er signtficantly in their modes of biochemical and physiological disposition of chemicals. This assumption disregards the fact that the rate of metabolism of mice is about 12 times that of humans, and the comparative lifetimes differ by about a factor of 35. Detailed examination of the comparative chemistry of mice and humans is revealing an increasing number of instances of differences in the carcinogenicity of substances arising from the high rate of metabolism of mice. An example is trichloroethylene (TCE). It caused liver tumors in B,C,F, mice and has been declared a carcinogen by EPA [ 1I]. In contrast, the American Conference of Governmental and Industrial Hygienists has stated that TCE is not a carcinogen [12]. Millions of workers have been exposed to it without exhibiting excess cancer. Why is there a difference between human experience and mouse studies? Because there are differences in metabolism for mice and men. In TCE is rapidly converted to mice, trichloroacetic acid, which induces cancer in the mouse liver [13]. In the rat, metabolism is slower, the concentration of acid is small and no liver cancer results. Human metabolism of TCE is also slow; low levels of acid do not affect liver cells in vitro. A fifth assumption is related to the earlier fourth one: The routine extrapolation of results on mice to humans assumes that humans are 12 times more susceptible to possible carcinogens than are tumor-prone mice. Again the assumption is proving to be unreliable. An example is the comparative metabolism of butadiene. Butadiene is far more hazardous to mice than to rats. When mouse, rat and human liver cells were exposed to butadiene in vitro, it was the mouse liver cells that were affected [14]. In mice, butadiene is rapidly oxidized to an epoxide and then to a mutagenic diepoxide. In rat and human liver cells, conversion to the epoxide proceeds slowly and is followed by hydrolysis to form a nontoxic product. A sixth assumption is that: If a huge dose of a chemical can cause cancer, one molecule of it can cause cancer.

Commentary

The lack of validity of a linear extrapolation of effects of chemicals from MTDs to small ones has been already proven. In about one-third of the cases in which an MTD caused cancer, a dose of one-half the MTD did not. If tests were conducted with still smaller fractions of an MTD, it is likely that even more exceptions to the linear model would be observed. There exists implicitly a seventh assumption: Industrially produced chemicals are to be presumed carcinogenic until proven safe. Chemicals produced by nature are presumed to be benign. The truth is that some of the most toxic substances that have ever been produced are created by nature. Many of them are employed either in defense or to stun or kill a potential source of food. Plants cannot run from enemies, and they are attacked by many organisms. Most plants survive because they have developed defensive mechanisms that include production of natural pesticides. Foods contain some or many of these natural pesticides. Bruce Ames and Lois Gold have studied this matter and published about it in the Proceedings of the National Academy of Sciences, in the AAAS journal Science [15] and elsewhere. The foliowing is a selection of some of their comments: About 99.9 percent of all pesticides in the human diet are natural pesticides from plants All plants produce toxins to protect themselves against fungi, insects, and animal predators such as humans. Tens of thousands of these natural pesticides have been discovered, and every species of plant contains its own set of different toxins, usually a few dozen. When plants are stressed or damaged (when attacked by pests), they greatly increase their output of natural pesticides, occasionally to levels that are acutely toxic to humans. Surprisingly few of these thousands of plant toxins in our diet have been involved in animal cancer tests, but of those tested in at least one species of animal about half. are carcinogenic. The natural pesticides that are rodent carcinogens occur naturally in at least 53 different food items including fruits and vegetables Examples of food items having such high levels include apple, cabbage, lettuce, orange juice and potato. Almost every plant product in the supermarket probably contains natural carcinogens at levels that are commonly hundreds or thousands of times higher than those of synthetic pesticides, The absence of a high incidence of cancer attributable to naturally occurring rodent carcinogens in our diets casts doubt on the significance of far lower exposures to synthetic chemicals

I repeat that last sentence: “The absence of a high incidence of cancer attributable . . to naturally occurring rodent carcinogens in our diets . . . casts doubt on the significance of far lower exposures to synthetic chemicals . .”

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On the basis of some of the EPA risk assessment assumptions, the widely-used fungicide captan was declared a carcinogen in 1977. It is one of the important pesticides that might be banned. The experiments that led to its classification as a carcinogen are described in the official federal publication, “Environmental Health Perspectives Supplements” [8]. Both rats and mice were tested. It was concluded that there was no convincing evidence that captan caused tumors in the rats. The B,C,F, mice were given the captan incorporated in feed at doses of either 8000 or 16,000 parts per million. During their lifetimes the high-dose animals consumed about their weight of captan. Of the male mice receiving high doses, 3 of 46 developed carcinomas; only 1 of 43 of the low-dose males did so. Of the females, 3 of 48 high-dose animals developed carcinomas; none of the lowdose females did. Taken together, 6 high-dose animals developed carcinomas, while one lowdose animal did. The numbers indicate that there is a threshold and that captan is not a carcinogen at levels relevant to humans. In its risk assessments EPA continues to rely heavily on the arbitrary ad hoc assumptions that I have described. It pays little heed to human epidemiology. In the 1970s great concern about a possible cancer epidemic resulted in efforts to identify industrial substances that might cause cancer. The major chemical companies expanded their health and safety programs. Monitoring of levels of exposures in industrial plants was increased. Data bases on health, morbidity and mortality of more than a million workers have been maintained. In general, in spite of large chronic exposures to chemicals that occurred in earlier decades, the health and longevity of the workers have been similar to those of the comparable age group of the general population. There have been isolated examples in industry of cancer caused by intense exposures to chemicals, but there has been no major incidence of cancer. Actual industrial occurrence of carcinogenicity contrasts sharply with the hazards inferred as a result of rodent experiments. The rodent tests imply that more than half of thousands of industrial chemicals are carcinogens. Experience in the chemical industry indicates that comparatively few chemicals have caused cancer. Sir Richard Doll, the distinguished British toxicologist, has reviewed world-wide human data and concluded that, apart from a few known

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chemicals that are now tightly controlled, the risks to which chemical workers have been exposed “have not been notably greater than those to which others have been exposed in other walks of life” [16]. In sum, the results of carcinogenicity experimentation with rodents have been grossly misleading. Before additional hundreds of billions of dollars of public funds are wasted and our food supply is curtailed, EPA should be required to re-evaluate and revise its methods of risk assessment and risk management.

ABELSON

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1994; 22: 90-102.

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Food and Drug Administration Pesticide Program. J Assoc Off Anal Chem 1992; 75. Block G, Patterson B, Subar A. Fruits, vegetables and cancer prevention: A review of the epidemiological evidence. Nutr Cant 1992; 18: l-29. Gianessi L. The quixotic quest for chemical-free farming. Issues Sci Technol 1993: Fall: 29936. Knutson RD, Hall CR, Smith EG, Cotner SD, Miller JW. Economic Impacts of Reduced Pesticide Use on Fruits and Vegetables (Executive Summary). Texas: American Farm Bureau Research Foundat&; 1993. Cameron TP. Hickman, RL. Kronreiah MR. Tarone RE. History, survival, and growth patterns of B6C3Fl mice and F344 rats in the National Cancer Institute carcinogenesis testing program. Fundam Appl Toxic01

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Gori GB, Adjudicating cancer causation: scientific, political, and legal conflicts. Regul Toxic01 Pharmacol 1991;

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Report of the Ad Hoc Working Group on Oil/Gavage in Toxicology Washington, DC: The Nutrition Foundation 1983. USEPA. Health Assessment for Document Trichloroethylene. Washington, DC: US Environmental Protection Agency; 1985. American Conference of Governmental and Industrial Hygienists Notice of intended change-trichloroethylene. Appl Occup Environ Hyg 1992; 7(1 I): 786-790.

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Green T. ChhYroethylenes: A mechanistic approach to human risk evaluation Annu Rev Pharmacol Toxicol

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Csanady GA, Bond JA. Species differences in the biotransformation of I,3 butadiene to DNA-reactive eposides: Role in cancer risk assessment. CIIT Activities 1991; II: l-10. Ames BN, Gold LS. Too many rodent carcinogens: Mitogenesis increases mutagenesis. Science 1990; 249: 970-97 1. Doll R. Hazards of cancer in the chemical industry. BIBRA Bull 1991; 30: 1833188.

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Haseman JK, Crawford DD, Huff JE, Boorman GA, McConnell EE. Results from 86 two-year carcinogenicity studies conducted by the national toxicology program. J Environ Health 1984; 14: 621-639. National Institutes of Health. Environmental Health Perspectives: Compendium of Abstracts from LongTerm Cancer Studies Reported by the National Toxicology Program from 1976 to 1992. Research Triangle Park, NC: National Institute of Environmental Health Sciences; 1993: 101 (Suppl. 1). Larson JL, Wolf DC, Butterworth E. Induced cytotoxicity and cell proliferation in the hepatocarcinogenicity of chloroform in female B,C,F, mice: Comparison of administration by gavage in corn oil vs ad libitum in drinking water. Fundam Appl Toxicol

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