Chapter 24
Pesticide Residues and Food Safety Downloaded from pubs.acs.org by UNIV OF MASSACHUSETTS AMHERST on 09/25/18. For personal use only.
Food Safety Assessment for Various Classes of Carcinogens T. W. Fuhremann Monsanto Agricultural Company, St Louis, MO 63167 One of the objectives of this conference is to discuss improvements which could be made in the risk assessment process and government regulation of dietary exposure to pesticides. Important aspects of this discussion are the questions of how much confidence the scientific community has in the process, how the public perceives the assessments and how they respond. I will point out some areas for improvement which could lead to new initiatives in this area. Concern over dietary residues is primarily directed towards carcinogenic effects because current regulatory policy is grounded in the theory that cancer is a non-threshold disease. If true, this means there could be a cancer risk at any exposure level no matter how small. In contrast, other diseases associated with chemical exposures are considered to have exposure thresholds below which there is no risk. Therefore, we are usually concerned about carcinogens presenting a risk at exposures much lower than those associated with other diseases. I will therefore focus my comments on assessments for carcinogenicity, particularly those aspects related to identification and ranking of carcinogens. Rarely, if ever, do we have reliable human data to evaluate the carcinogenic potential of pesticides. Human epidemiology data are limited because it would be necessary to detect small increases of cancer in a population where one of four people now die of cancer from all causes. To illustrate this point we can consider a population of one million people with a life long chemical exposure at a level which is calculated to produce a hypothetical upper limit increased risk of one per 100,000 people or lxl0~ . We would estimate therefore, that at most, 10 of these million exposed people would develop cancer. If these ten people died of the disease the total cancer deaths for the million people would be 250,010. Thus, we are unable to detect small increases unless there is a very unusual form of cancer. We also are unable to measure reductions in cancer due to regulation or other control strategies. 5
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Given the fact that reliable human epidemiology data is seldom avail able and that direct human testing is not possible, we have had to rely on data derived from rodent bioassays to identify most carcinogens. If evidence of carcinogenicity is observed in these bioassays, that data can be integrated with human exposure information to produce qualitative judgements and quantitative estimates of risk for humans exposed to the chemical. Thus, the laboratory animal has become the cornerstone of carcinogen evaluation and regulation. The animal evidence for carcinogenicity is classified by regulatory agen cies as to the confidence in the conclusion which can be drawn from the data. Thus, a chemical which reproducibly causes malignant tumors or unusual tumors or early age tumors is considered to have stronger evidence than a chemical which produces only benign tumors in a single animal species or which has not been tested as thoroughly (7). Regulatory policy avows that strong evidence for animal carcinogenicity increases the likeli hood that the chemical is also a human carcinogen. This is reasonable as a prudent public health policy. However, from a scientific viewpoint, animal evidence cannot be considered an infallible predictor of human carcinogeni city. The rodent carcinogenicity bioassay has not been validated i.e. the false negative and false positive rate has not been determined and perhaps can not be determined. Over 1000 chemicals have been tested for carcinogenicity. Several esti mates suggest that 40-60% of these chemicals are to be considered animal carcinogens (2-5). A small number of these animal carcinogens are known to be human carcinogens because reliable human data is available. Con versely a small number of these animal carcinogens are considered unlikely to be human carcinogens because of their mode of action or conditions of exposure. However, the vast majority of animal carcinogens have unknown human carcinogenic activity and are considered to be at least suspect human carcinogens. The EPA uses a now well-known alphabetic scheme for categorizing carcinogenic evidence (7). Categories A and B require some actual human evidence while categories B and C are based solely on animal data. As of October 1989 (6), EPA had assigned categories for 89 pesticides (Table I). 1
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Table I. EPA CATEGORIZATION OF CARCINOGENIC POTENTIAL OF PESTICIDES (October 1989) CATEGORY DESCRIPTION NUMBER 0 A HUMAN Bl PROBABLE HUMAN 2 B2 PROBABLE HUMAN 26 C POSSIBLE HUMAN 45 D NOT CLASSIFIABLE 11 Ε NON-CARCINOGENIC 5
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None of these are considered to be known human carcinogens. The two B« chemicals for which limited human evidence is available are cadmium and acrylonitrile which are not primarily used as pesticides. Only five of the 89 chemicals are considered non-carcinogenic (category E). Thus the majority (80%) of classified pesticide carcinogens have been placed in category B or C and are called "probable" or "possible" human carcinogens. I suggest that these descriptions have little or no differential meaning for the general public. However, most scientists would conclude that there are dramatic hazard differences between various B carcinogens or various C carcinogens. The data which is generated for pesticides often does not fit neatly into these categories. The EPA is currently reviewing this categorization scheme to determine if a more discriminating and informative system can be de vised. Under consideration is inclusion of a category for animal carcinogens which are unlikely to be human carcinogens. Such a category is appropriate in light of recent scientific developments which support that conclusion for some chemicals. Dr. John Weisburger has suggested that there are a number of proper ties common to most known human carcinogens (7). These carcinogens, when tested in animals, produce tumors in several animal species, in high yield and at relatively low dosage levels, compared to the maximum tolerated dosage. Furthermore, these carcinogens produce tumors in 12-18 months. They are also clearly genotoxic in multiple assays. Many animal carcinogens of unknown human carcinogenic potential do not share these properties. This would suggest that a systemic study of known human carci nogens and an agreed upon panel of non-carcinogens might yield informa tion that could be used to validate the chronic bioassay or redesign the bioassay so that it would be more discriminating in identifying potential human carcinogens. Potency is one indicator of carcinogenic concern and a means of rank ing various carcinogens. Table II shows the range of (X* potency values calculated for the carcinogenic pesticides categorized by EPA (6). The Qj* is the 95% upper confidence limit on the slope of the dose-response curve. Multiplication of the Qj* by exposure produces the 95% upper confidence limit on risk. The larger numbers represent more potent carcinogens. There is a large range of potency (five orders of magnitude for the B pesticides). There is also considerable overlap between the three categories. There is, therefore, no relationship between the EPA potency values and the alpha betic hazard classification. Potency values can be very informative to both 2
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Table Π. EPA POTENCY RANGES FOR CARCINOGENIC PESTICIDES 1
Bl B2 C
[MG/KG/ΡΑΥΓ 6 TO 0.5 67 TO .002 0.3 TO .003
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scientists and the public. These values allow the comparison of potency of various carcinogens on an absolute scale so that the chemicals can be ranked independently of exposure and predicted human carcinogenic potential. Due to the uncertainty in predicting human carcinogenic potential, it would be prudent to create a carcinogen ranking scheme, based on potency, that includes all chemical carcinogens including pesticides. I have difficulty with potency expressed as values because they represent upper confidence bounds. I have compared chemicals where the most probable potency values for chemical X are higher than for chemical Y, but the 95% upper confidence values are higher for chemical Y than chemical X. This could lead to an inappropriate potency ranking. Furthermore Q.* values are essentially determined by the dose levels used in the rodent bioassay while the tumor response is inconsequential. I would prefer to use an expression such as the dose causing a 1% increase in tumor response which can be determined directly from the animal data and does not involve as much uncertainty as determination of the Q^* value. In any event potency should be an important consideration in ranking carcinogens. The discipline of carcinogen identification and risk assessment is fraught with uncertainty which leads to regulatory fiat, controversy and inevitable delays for regulators, registrants and the public. At present the general public response to carcinogenic proclamations fluctuates between outrage, skepticism, confusion, frustration and apathy. Outrage, when justified, is healthy because it precipitates action. Apathy, as implied by the phrase "If everything is a carcinogen then nothing is a carcinogen," can be dangerous. The public is frustrated because they don't know when to be concerned and when not to be concerned. The answer to this dilemma will come from a reduction in uncertainty and the resultant controversy which should lead to renewed confidence in the use of pesticides and the regulatory process. I believe that it should be our common goal to improve our ability to reliably determine, prioritize and communicate human cancer risks. There are a number of research opportunities which will help us to achieve this goal. I suggest that it is time to reexamine the chronic bioassay. If the bioassay produces a 40-60% positive rate, then it might be more efficient to design the assay so that it is less sensitive to those chemicals which are unlikely to be human carcinogens or those which are of low potency. For example, consideration could be given to testing at lower maximum dosage levels or shortening the duration of the assay so that it only responds to the more potent chemicals. A program to validate or redesign the chronic bioassay could be appropriately conducted by the National Toxicology Program. Another area that should be given serious consideration is development of actual human data on adsorption, distribution, metabolism and excretion. This information could be derived from accidental exposures, occupational exposures, in vitro studies with human tissues or carefully controlled administration to human volunteers. Such data would allow appropriate selection of animal bioassay models and comparison of metabolic and
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mechanistic information for rodents and humans. This information should be developed by manufacturers for proprietary chemicals and government agencies or industry associations for commodity chemicals. It is imperative that we place greater emphasis on the development of information which will provide an improved basis for judging the human relevance of rodent bioassays producing a carcinogenic response. Development of meaningful tools which appropriately determine and convey relative degrees of risk is essential to ensuring public confidence in the regulatory process. Regulators must be prepared to utilize this information in order to provide an incentive for its development. I believe that the time is right for the establishment of a national or international task force to study and make recommendations on these issues. If we fail to do this, the development of many new chemical technologies which contribute to health, the high standard of living, and economic growth of this country will be severely limited. Literature Cited 1. U.S. Environmental Protection Agency; 1986 Guidelines for Carcinogen Risk Assessment, Federal Register 51, 33992-34003. 2. Haseman, J.; Crawford, D. J. Toxicol. Environ. Health 1984, 14, 621-639. 3. Purchase, I. Br. J. Cancer 1980, 41, 454-468. 4. Salsburg, D. Fundamental and Applied Toxicology 1983, 3(1-2), 63-66. 5. Tomatis, L.; Agthe, C.; Bartsch, H.; Huff, J.; Montesano, R. S.; Walker, E.; Willbourn, J. Cancer Research 1978, 38, 877-885. 6. U.S. Environmental Protection Agency; List of Chemicals Evaluated for Carcinogenic Potential Memorandum; From Engler, R., October 20, 1989. 7. Weisburger, J. Japanese Journal of Cancer Research 1985, (Gann) 76, 1244-1246. RECEIVED August 26, 1990
