Gaining a broad perspective about the vast number of chemicals to which humans are exposed can be helpful when setting research and regulatory priorities. 61 Rodent cancer tests provide little information about how a chemical causes cancer or about low-dose risk. The assumption that synthetic chemicals are hazardous has led to a bias in testing, such that synthetic chemicals account for 77 percent (432 of 559) of the chemicals tested chronically in both rats and mice. [See Appendix Table IV.] The natural world of chemicals has never been tested systematically. One reasonable strategy is to use a rough index to compare and rank possible carcinogenic hazards from a wide variety of chemical exposures at levels that humans typically receive, and then to focus on those that rank highest. 62 Ranking is a critical first step that can help to set priorities for selecting chemicals for long term cancer tests, studies on mechanism, epidemiological research and regulatory policy. Although one cannot say whether the ranked chemical exposures are likely to be of major or minor importance in human cancer, it is not prudent to focus attention on the possible hazards at the bottom of a ranking if, using the same methodology to identify hazard, there are numerous common human exposures with much greater possible hazards. Our analyses are based on the HERP index (Human Exposure/Rodent Potency), which indicates what percentage of the rodent carcinogenic potency (TD50 in mg/kg/day, i.e. dose to give 50 percent of test animals tumors) a human receives from a given daily lifetime exposure (mg/kg/day). 63 [See Appendix Table Va and Vb.] A ranking based on standard regulatory risk assessment would be similar.

Overall, our analyses have shown that HERP values for some historically high exposures in the workplace (e.g., butadiene and tetrachloroethylene) and some pharmaceuticals (e.g., clofibrate) rank high, and that there is an enormous background of naturally occurring rodent carcinogens in typical portions of common foods that cast doubt on the relative importance of low-dose exposures to residues of synthetic chemicals such as pesticides. 64 A committee of the National Research Council/National Academy of Sciences recently reached similar conclusions about natural vs. synthetic chemicals in the diet, and called for further research on natural chemicals. 65

The possible carcinogenic hazards from synthetic pesticides (at average exposures) are minimal compared to the background of nature's pesticides, though neither may be a hazard at the low doses consumed. [See Appendix Table Va and Vb.] Appendix Table V also indicates that many ordinary foods would not pass the regulatory criteria used for synthetic chemicals. For many natural chemicals the HERP values are in the top half of the table, even though natural chemicals are markedly underrepresented because so few have been tested in rodent bioassays. Caution is necessary in drawing conclusions from the occurrence in the diet of natural chemicals that are rodent carcinogens. It is not argued here that these dietary exposures are necessarily of much relevance to human cancer. Our results call for a reevaluation of the utility of animal cancer tests in protecting the public against minor hypothetical risks.

It is often assumed that because natural chemicals are part of human evolutionary history, whereas synthetic chemicals are recent, the mechanisms that have evolved in animals to cope with the toxicity of natural chemicals will fail to protect against synthetic chemicals. This assumption is flawed for several reasons. 66

a) Humans have many natural defenses that buffer against normal exposures to toxins, 67 and these are usually general, rather than tailored for each specific chemical. Thus they work against both natural and synthetic chemicals. Examples of general defenses include the continuous shedding of cells exposed to toxins - the surface layers of the mouth, esophagus, stomach, intestine, colon, skin and lungs are discarded every few days; DNA repair enzymes, which repair DNA that was damaged from many different sources; and detoxification enzymes of the liver and other organs which generally target classes of toxins rather than individual toxins. That human defenses are usually general, rather than specific for each chemical, makes good evolutionary sense. The reason that predators of plants evolved general defenses is presumably to be prepared to counter a diverse and ever-changing array of plant toxins in an evolving world; if a herbivore had defenses against only a set of specific toxins, it would be at a great disadvantage in obtaining new food when favored foods became scarce or evolved new toxins.

b) Various natural toxins, which have been present throughout vertebrate evolutionary history, nevertheless cause cancer in vertebrates. 68 Mold toxins, such as aflatoxin, have been shown to cause cancer in rodents and other species including humans [see Appendix Table IV.] Many of the common elements are carcinogenic to humans at high doses (e.g., salts of cadmium, beryllium, nickel, chromium and arsenic) despite their presence throughout evolution. Furthermore, epidemiological studies from various parts of the world show that certain natural chemicals in food may be carcinogenic risks to humans; for example, the chewing of betel nuts with tobacco has been correlated with oral cancer.

c) Humans have not had time to evolve a "toxic harmony" with all of their dietary plants. The human diet has changed markedly in the last few thousand years. Indeed, very few of the plants that humans eat today (e.g., coffee, cocoa, tea, potatoes, tomatoes, corn, avocados, mangoes, olives and kiwi fruit) would have been present in a hunter-gatherer's diet. Natural selection works far too slowly for humans to have evolved specific resistance to the food toxins in these newly introduced plants.

d) DDT is often viewed as the typically dangerous synthetic pesticide because it concentrates in the tissues and persists for years, being slowly released into the bloodstream. DDT, the first synthetic pesticide, eradicated malaria from many parts of the world, including the U.S. It was effective against many vectors of disease such as mosquitoes, tsetse flies, lice, ticks and fleas. DDT was also lethal to many crop pests, and significantly increased the supply and lowered the cost of food, making fresh nutritious foods more accessible to poor people. DDT was also of low toxicity to humans. A 1970 National Academy of Sciences report concluded: "In little more than two decades DDT has prevented 500 million deaths due to malaria, that would otherwise have been inevitable." 69 There is no convincing epidemiological evidence, nor is there much toxicological plausibility, that the levels of DDT normally found in the environment are likely to be a significant contributor to cancer. DDT was unusual with respect to bioconcentration, and because of its chlorine substituents it takes longer to degrade in nature than most chemicals; however, these are properties of relatively few synthetic chemicals. In addition, many thousands of chlorinated chemicals are produced in nature70 and natural pesticides also can bioconcentrate if they are fat soluble. Potatoes, for example, naturally contain the fat soluble neurotoxins solanine and chaconine, which can be detected in the bloodstream of all potato eaters. High levels of these potato neurotoxins have been shown to cause birth defects in rodents. 71

e) Since no plot of land is immune to attack by insects, plants need chemical defenses - either natural or synthetic - to survive pest attack. Thus, there is a trade-off between naturally occurring pesticides and synthetic pesticides. One consequence of disproportionate concern about synthetic pesticide residues is that some plant breeders develop plants to be more insect-resistant by making them higher in natural toxins. A recent case illustrates the potential hazards of this approach to pest control: When a major grower introduced a new variety of highly insect-resistant celery into commerce, people who handled the celery developed rashes when they were subsequently exposed to sunlight. Some detective work found that the pest-resistant celery contained 6,200 parts per billion (ppb) of carcinogenic (and mutagenic) psoralens instead of the 800 ppb present in common celery. 72