A critique of the use of the maximum tolerated dose in bioassays to assess cancer risks from chemicals.

The maximum tolerated dose (MTD) regimen for testing substances for their ability to induce cancer and other chronic diseases in laboratory rodents has been required by governmental authorities for several decades. Cancer researchers originally suggested the MTD approach and it was then adopted by the FDA and EPA. The intention was to detect the ability of any substance under any circumstances, including the most extreme, to induce cancer in laboratory rodents. We question the validity of using the MTD in animal bioassays to evaluate risk for human cancer. The paradox is that the safer the chemical, the higher the MTD, but the higher the MTD, the more likely that biochemical distortions will result and cause cellular injury, abnormal cell replication, toxic hyperplasia, and toxicity-induced cancer. All chemicals are toxic at some dose, whether relevant to anticipated human exposure or vastly exceeding it. New approaches to cancer-testing lifetime bioassays are needed. A minimally toxic dose is defined and suggested to avoid specific tissue toxicity detected by clinical or pathology examination in animals subchronically exposed to the test compound for 90 days. The highest subtoxic dose that can be tolerated by test animals over a long period of time is suggested as being more appropriate for carcinogenicity bioassays.

The evaluation of the carcinogenicity of environmental substances.

A review of the current status of carcinogenicity assessment leads to a number of observations that raise specific questions about the conduct and techniques of these bioassays. An approach is suggested that avoids many of the scientific controversies associated with the use of excessively high doses that cause secondary toxicity, leading to a promoter-like effect. Recommendations are made to utilize toxicokinetic data that relate metabolic characteristics of a chemical to its potential carcinogenic effects.

Food safety and public health: interaction of science and law in the federal regulatory process.

The programs of the Food and Drug Administration (FDA), which operates under a broad mandate of regulatory authority provided by the Congress in the form of the Food, Drug, and Cosmetic Act, demonstrate the way in which science and law interact to protect public health through the regulatory process. In particular, sections 402, 406, and 409 of the Act provide the means for regulating both new and old food products approved for use by the petition process as well as foods which present a potential hazard because of environmental accidents which result in residues of undesirable or dangerous chemical substances. The episodes of foods contaminated with polychlorinated biphenyls (PCBs) or polybrominated biphenyls (PBBs), and the manner in which action levels or guidelines were developed to regulate the allowable levels of these chemicals in foods, describe the pragmatic way in which FDA protects public health by restricting the allowable levels of chemical substances in foods.

Cancer in humans: exposures and responses in a real world.

Cancer causation in humans is at least a three-dimensional problem too often viewed from only two dimensions, especially as far as the two-dimensional results (dose versus response) of cancer induction tests in animals are viewed. The expression of a cancer represents a critical convergence of additional factors in the third dimension which include metabolic variables, many of which may involve secondary mechanisms. Many of these mechanisms are involved in the causation pattern of cancer in humans and can be expected to operate within the dose-response considerations observed in the fields of toxicology and pharmacology. The expression of critical reactions of cells in relatively unprotected tissues may occur more readily after exposures involving fewer molecules of one "carcinogen" as compared to another "carcinogen". Results from animal tests may have limited human relevance in some instances and detract us from consideration of the more fundamental factors involved in the etiology of human cancer. A precipitous rush to "zero tolerances" for all animal carcinogens may impair our efforts to prevent the worst "causes" of cancer induction in humans.

Human safety considerations from the use of anabolic agents in foodproducing animals.

The various anabolic agents used in food-producing animals may differ in terms of toxicological considerations related to evaluating human safety. Aside from initial toxicological testing, after chemical characterization of the compound to be administered and its related metabolites expected to occur as residues in food, most synthetic anabolic agents are subjected to chronic/carcinogenicity testing because of usage pattern likely to lead to the occurrence of residues in derived edible products. Initial testing requirements include acute and subchronic studies in appropriate rodent species including a reproduction test with the first generation offspring tested for 90 days post-weaning. This subchronic study serves to indicate potential problems with reproductive performance, foetal toxicity, birth deformities, and other chronic or preneoplastic conditions. The Food and Drug Administration (FDA) may grant approval for certain usages of specific compounds using a 2.000-fold safety margin in relation to a "no deleterious effect" level from the subchronic studies, with upper residue limits of 0.1 ppm in tissue and 0.01 ppm in milk or eggs if there are no indications that further testing should be required. If higher residue limits are requested, the petitioner must perform lifetime testing in two rodent species including in utero exposure and a minimum of three dose levels. Other rodent offspring should be carried for a total of three generations. A six to twelve month study in a non-rodent population is required. Teratology studies might be rquired in at least two species. If no carcinogenic potential is observed, a 100-fold safety margin in relation to the no effect level is generally accepted as the safe exposure level for residues. Should a statistically significant increase in tumors be observed in the test animals as compared to controls, the compound will be classified as a carcinogen or a suspect carcinogen depending on histopathological observations...

Food exposures to lead.

Exposures to lead have emanated from various sources, including food, throughout human history. Occupational and environmental exposures (especially pica) appear to account for much of the identified human disease, however, food-borne exposures deserve further investigation. Lead residues in food can result from: biological uptake from soils into plants consumed by food animals or man, usage of lead arsenate pesticides, inadvertent addition during food processing, and by leaching them improperly glazed pottery used as food storage or dining utensils. Estimates of total dietary exposure should reflect frequency distribution data on lead levels in specific food commodities in relation to the quantities actually ingested by various sample populations to distinguish degrees of risk associated with particular dietary habits. Earlier estimates of average total dietary intake of lead by adults have been reported to range from above 500 mug/day downward with more recent estimates suggesting averages of 200 mug/day or lower. The strengths and weaknesses of these data are discussed along with analytical and sampling considerations. FDA programs related to food surveillance, epidemiology, and toxicological investigation are briefly described.