The toxicological significance of exposures to synthetic chemicals is examined in the context of exposures to naturally occurring chemicals. We calculate that 99.99% (by weight) of the pesticides in the American diet are chemicals that plants produce to defend themselves. Only 52 natural pesticides have been tested in high-dose animal cancer tests, and about half (27) are rodent carcinogens; these 27 are shown to be present in many common foods. We conclude that natural and synthetic chemicals are equally likely to be positive in animal cancer tests. We also conclude that at the low doses of most human exposures the comparative hazards of synthetic pesticide residues are insignificant.

This paper proposes that the mammalian immune response known as "allergy" evolved as a last line of defense against the extensive array of toxic substances that exist in the environment in the form of secondary plant compounds and venoms. Whereas nonimmunological defenses typically can target only classes of toxins, the immune system is uniquely capable of the fine-tuning required to target selectively the specific molecular configurations of individual toxins. Toxic substances are commonly allergenic. The pharmacological chemicals released by the body's mast cells during an IgE antibody-mediated allergic response typically cause vomiting diarrhea, coughing, tearing, sneezing, or scratching, which help to expel from the body the toxic substance that triggered the response; individuals frequently develop aversions to substances that have triggered such responses. A strong allergic response often includes a decrease in blood pressure, which slows the rate at which toxins circulate to target organs. The immune system identifies as toxic the following kinds of substances: (1) those low-molecular-weight substances that bind covalently to serum proteins (e.g., many plant toxins); (2) nontoxic proteins that act as carriers of toxins with low molecular weights (e.g., plant proteins associated with plant toxins); (3) specific substances of high molecular weight that harmed individuals in ancestral mammalian populations for a span of time that was significant from the standpoint of natural selection (e.g., the toxic proteins of bee venom. Substances that bind covalently to serum proteins generally are acutely toxic, and because many of these substances also bind covalently to the DNA of target cells, they are potentially mutagenic and carcinogenic as well. Thus, by protecting against acute toxicity, allergy may also defend against mutagens and carcinogens. The toxic hypothesis explains the main phenomena of allergy; why IgE-mediated allergies usually occur within minutes of exposure to an allergen and why they are often so severe; why the manifestations of allergy include vomiting, diarrhea, coughing, sneezing, scratching, tearing, and a drop in blood pressure; why covalent binding of low-molecular-weight substances to serum proteins frequently causes allergy; why allergies occur to many foods, pollens, venoms, metals, and drugs; why allergic cross-reactivity occurs to foods and pollen from unrelated botanical families; why allergy appears to be so capricious and variable; and why allergy is more prevalent in industrial societies than it is in foraging societies. This hypothesis also has implications for the diagnosis, prevention, and treatment of allergy.

The toxicology of synthetic chemicals is compared to that of natural chemicals, which represent the vast bulk ofthe chemicals to which humans are exposed. It is argued that animals have a broad array of inducible general defenses to combat the changing array of toxic chemicals in plant food (nature's pesticides) and that these defenses are effective against both natural and synthetic toxins. Synthetic toxins such as dioxin are compared to natural chemicals, such as indole carbinol (in broccoli) and ethanol. Trade-offs between synthetic and natural pesticides are discussed. The finding that in high-dose tests, a high proportion of both natural and synthetic chemicals are carcinogens, mutagens, teratogens, and clastogens (30-50% for each group) undermines current regulatory efforts to protect public health from synthetic chemicals based on these tests.

Sperm are vectors of disease. During mammalian insemination bacteria from the male and female genitalia regularly cling to sperm tails and are transported to the uterus. I propose that menstruation functions to protect the uterus and oviducts from colonization by pathogens. Menstrual blood exerts mechanical pressure on uterine tissue, forcing it to shed, and delivers large numbers of immune cells throughout the uterine cavity, directly combating pathogens. The mechanisms of menstruation show evidence of adaptive design. Spiral arteries that open to the lining of the uterus trigger menstruation by abruptly constricting, which deprives the local tissue of blood, and then abruptly dilating, which causes blood to force loose the necrotic tissue. Menstrual blood flows easily, unlike blood at most wound sites, because it lacks the normal level of clotting factors. Overt (externally visible) or covert (not externally visible) menstruation has been documented in many species of primate, including Old World monkeys and apes, New World monkeys, and prosimians, as well as in various species of bat and insectivore. The antipathogen hypothesis predicts that: (1) menstruation (overt or covert) is either universal or nearly so among mammalian species; (2) if the latter, then the existence of menstruation among species varies inversely with the probability of becoming pregnant per estrous cycle (menstruation would be especially adaptive in species with significantly less than 100% probability of becoming pregnant per estrous cycle); (3) among menstruating species, the average degree of menstrual bleeding for a given species is a function of the factors affecting menstruation's costs and benefits--in particular, the degree of bleeding is positively correlated with the average body size and sexually transmitted pathogen load of that species (profuse bleeding would be especially adaptive in large-bodied species with either promiscuous breeding systems or continuous sexual receptivity); and (4) other forms of normal uterine bleeding--proestrous, periovulatory, implantation, and postpartum--also have an antipathogen function. The hypothesis presented in this article has implications for the diagnosis, treatment and prevention of uterine infection and, therefore, for the prevention of pathogen-induced infertility. The uterus appears to be designed to increase its bleeding if it detects infection: Human uteri that become infected (or otherwise inflamed) bleed more profusely, bleed on more days per cycle, and often bleed intermittently throughout the cycle. Thus artificially curtailing infection-induced uterine bleeding may be contraindicated.

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