Even when given the same exposure to a toxin, individuals vary in their responses. The causes of variation include genetic, nutritional, age and sex, metabolic activity level, life stage, or exposure history leading to lesions, sensitization, or enzyme induction.
Several examples in humans will show that individuals of the same species can have large genetic differences in responses to toxins. Many Orientals are genetically predisposed to a more rapid metabolism of ethanol to acetalydehyde. Since it is the metabolite that is responsible for many of the symptoms of ethanol intoxication, these people react strongly to even small doses, becoming flushed and uncomfortable. Another example is in the inherited propensity that some people have toward specific cancers, such as retinoblastoma, or skin or colon cancer. These people have inherited one of the ''hits'' required to convert a normal cell into a cancerous one. In a third example, millions of persons throughout the world have red blood cells with defects in their respiration pathways, such as a deficiency in glucose-6-phosphate dehydrogenase. These cells are not efficient in maintaining glutathione, which protects against peroxide attacks. People with this type of problem are especially sensitive to red blood cell hemolysis (breakdown) from certain chemicals, such as aspirin and naphthalene, and from substances in some foods, such as fava beans. This is an X-linked trait, exhibited only in males, who inherit it from their mothers (Section 6.1.2).
The sex of an animal can have a great influence as well. Male mice are much more sensitive than females to chloroform, possibly because males have a much higher concentration of cytochrome P450. Female rats are more sensitive than males to certain organo-phosphate pesticides. However, castration and hormone treatment render the males more sensitive.
Young animals are typically 1.5 to 10 times as sensitive to toxins as adults, possibly due to underdeveloped immunity or detoxification mechanisms. Malathion is about 28 times more toxic to newborn rats than to adults. However, this is not always the case. DDT is about 20 times less toxic to newborns, and Dieldrin was about 4.5 times less toxic. The young may absorb differently, and their blood-brain barrier is less efficient.
Preexisting disease can affect person's response to a toxin in several ways. If the disease affects the kidney or liver, it may affect the half-life of a compound by changing the rate of biotransformation or excretion. Of course, disease can also have an indirect effect by rendering the person more vulnerable to any type of additional damage.
The relationship between nutrition and toxicity is now known to be a major factor affecting toxic response. The effect occurs through altered absorption and renal function and by affecting toxin distribution in tissues. Fasting or low-protein diets may reduce cytochrome P450 activity. This can either increase toxicity (e.g., DDT) or decrease it (e.g., chloroform). Lipids in the diet delay absorption of lipophobic substances and enhance it for lipophilic substances. Essential fatty acids, such as linoleic acid, are important to the cytochrome P450s. Fatty tissues can store lipophilic toxins away from receptors. Thus, obesity actually protects against chronic toxicity of these compounds. However, high-fat diets enhance absorption and retention of lead and fluoride.
Epidemiological evidence indicates that vitamin A is protective against lung cancer. Exposing rats to PCB, DDT, and dieldrin significantly reduced the stores of vitamin A in the liver. However, vitamin A can be toxic at high levels. On the other hand, p-carotene, which is a precursor of vitamin A, is fairly nontoxic. Vitamins E and C are both important antioxidants. Lipophilic vitamin E acts to protect the membranes from free radicals and other oxidizers; vitamin C does the same in the cytoplasm. In addition, in vitro experiments suggest that vitamin C competes for nitrites, which are often found in preserved foods. This blocks their reaction with amines that would otherwise form carcinogenic nitroso compounds.
Zinc reduces the toxicity of lead and cadmium, and selenium is protective against cadmium and mercury. Also, selenium is a coenzyme for glutathione peroxidase. Together they destroy H2O2, which otherwise disrupts membranes by oxidation. Many metals are enzyme cofactors (e.g., iron is essential for the cytochrome P450 system).
Enzymes may be induced by previous exposure to the toxin or to other substances. This may persist for some time after the original exposure, affecting the response to a toxin until the induction effect dissipates.
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