Hazard Identification

Hazard identification is the determination of the known or potential health effects of consumption of the compound. In some cases, the need for toxicological testing can be predicted from the chemical structure based on known structure-activity relationships. Several chemical structures, such as n-nitroso or aromatic amine groups, are potentially carcinogenic. In many cases, manufacturers use this information to decide whether to go forward with expensive animal testing of their products. In vitro and short-term animal tests are also used before investing in long-term animal testing. These can include tests for mutagenicity, carcinogenecity, developmental toxicity, repro ductive toxicity, neurotoxicity, and immunotoxicity (3). However, for final approval of pesticides and food additives, the long-term animal bioassay is a key component in the hazard identification process. Table 2 lists the types of toxicological tests that are conducted using the animal model system. For food additives, the safety evaluation involves assigning a concern level to the additive, based on structural information and an estimate of exposure. The minimum toxicological testing required for each concern level is listed in Table 3.

Epidemiological studies, in which a positive association between exposure and disease has been observed, and case reports of accidental poisonings have provided convincing evidence of the human risk of various compounds. This has been the basis for the identification of many naturally occurring toxins, including ergot alkaloids, potato alkaloids, and toxic mushrooms.

Dose-Response Assessment

The dose-response assessment examines the relationship between the magnitude of the exposure and the probability of adverse effects. There are two approaches to dose-response assessments: a threshold approach for noncancer

Table 2. Types of Toxicological Tests

Acute tests (single exposure or dose)

Determination of median lethal dose (LD50)

Acute physiologic changes (blood pressure, pupil dilation, etc)

Subacute tests (continuous exposure or daily doses)

Three-month duration Two or more species (one nonrodent) Three dose levels (minimum) Administration by intended or likely route Health evaluation, including body weight, complete physical examination, blood chemistry, hematology, urinalysis, and performance tests Complete autopsy and histopathology on all animals to determine the presence of any tissue damage or cancerous tissues

Chronic tests (continuous exposure or daily doses) Two-year duration (minimum)

Two species selected for sensitivity from previous tests Two dose levels (minimum) Administered by likely route of exposure Health evaluation including body weight, complete physical examination, blood chemistry, hematology, urinalysis, and performance tests Complete autopsy and histopathology on all animals to determine the presence of any tissue damage or cancerous tissues

Special tests

Teratogenicity

Multigenerational reproduction feeding study (all aspects other than teratogenicity) Skin and eye effects Behavioral effects end points and a nonthreshold approach for cancer end points. The threshold is the level of exposure below which no adverse effects result. This approach is based on establishing a NOAEL, which is the highest dose in milligrams/ kilogram body weight that results in no detectable damage to the animal during chronic or subchronic testing. Safety factors are applied to the NOAEL to determine the RfD and the acceptable daily intake (ADI). The ADI values are used by the World Health Organization for pesticides and food additives to define "the daily intake of a chemical, which during an entire lifetime appears to be without appreciable risk on the basis of all known facts at that time." The safety factors, also called uncertainty factors, allow for differences in species and individual susceptibility to toxicity. A factor of 10 is used for each extrapolation (ie, from animals to humans, from a small number of animals to a population, from a short-term study to a chronic study) to result in a total safety factor of 100 to 1,000. The FQPA requires an additional 10-fold safety factor for pesticides if adverse effects on infants and children are unknown or increased compared to adults. Therefore, the RfD or ADI = NOAEL -h safety factors.

Dose-response models for cancer, which is considered to be a nonthreshold end point, can be categorized into two types. One type is the statistical or probability model, such as the log-probit and logit models. The other type is a mechanistic-based model, such as the one-hit, multistage, and linearized multihit models. A discussion of these models and the use of pharmacokinetic models to improve cancer risk assessment can be found in reference 25.

Exposure Assessment

For exposure assessment, estimates of the likely levels of human consumption of the particular food substance or the estimate of daily intake (EDI) must be made. It is necessary to know the following: (1) the amount of substance in the foods; (2) daily intake of each food containing the substance by consumers; and (3) the portion of the population that are consumers. The amount of a direct food additive in the foods will be based on the amount needed to obtain the desired effects of the additive and this will have been determined by the manufacturer petitioning for approval of the additive. For pesticides, tests are conducted to determine the level of pesticide that remains on the agricultural commodities after the pesticide is used in the production of that commodity. Food consumption surveys, food disappearance figures, and market basket surveys can be used to determine the EDI. However, food consumption surveys are most often used. The anticipated use and the toxicity of the compound will affect whether values for average consumers or heavy consumers (at or above 95th percentile for food intake) and values for the whole population or consumers only are used in the EDI. The daily intake of food consumed (kilograms per day) multiplied by the amount of the compound in the food (milligrams/ kilogram) provides an estimate of the amount of the compound (milligrams per day) that will be consumed. Guidelines on the estimations of exposure to food additives and chemical contaminants have been published by the U.S. FDA (26).

Table 3. Minimum Toxicological Testing of Food Additives Required by the U.S. Food and Drug Administration

Indirect food additives

Virtually nil exposure (<0.05 ppm) Acute oral study—rodent Insignificant exposure (>0.05 ppm) Acute oral study—rodent0

Subchronic feeding study (90-day)—rodent with in utero exposure Subchronic feeding study (90-day)—nonrodent

Multigenerational reproduction feeding study (minimum of 2 generations) with teratology phase—rodent" Teratology study

Short-term tests for carcinogenic potential6 Significant exposure (>~1 ppm) Acute oral study—rodent'

Subchronic feeding study (90-day)—rodent"

Lifetime feeding study (about 2 y)—rodent with in utero exposure for carcinogenesis and chronic toxicity

Lifetime feeding study (about 2 y)—rodent for carcinogenesis Short-term feeding study (at least 1 year)—nonrodent

Multigenerational reproduction feeding study (minimum of 2 generations) with teratology phase—rodent Teratology study"

Short-term tests for carcinogenic potential6 Metabolism studies6

Direct food additives

Concern level I (lowest concern) Short-term feeding study (at least 28 days)—rodent

Short-term tests for carcinogenic potential Concern level II Acute oral study—rodent?

Subchronic feeding study (90-day)—rodent Subchronic feeding study (90-day)—nonrodent

Multigenerational reproduction feeding study (minimum of 2 generations) with teratology phase—rodent Teratology study"

Short-term tests for carcinogenic potential Concern level III (highest concern) Acute oral study—rodent?

Subchronic feeding study (90-day)—rodentc

Lifetime feeding study (about 2 y)—rodent with in utero exposure for carcinogenesis and chronic toxicity

Lifetime feeding study (about 2 y)—rodent for carcinogenesis Short-term feeding study (at least 1 year)—nonrodent

Multigenerational reproduction feeding study (minimum of 2 generations) with teratology phase—rodent Teratology study"

Short-term tests for carcinogenic potential Metabolism studies6

Notes: If carcinogenicity is suspected as a problem, carcinogenicity studies will be done no matter what the circumstances. References to current guides on these toxicology studies are contained in the "Redbook" (24). "If indicated by available data or information. 'Suggested.

cIf needed as preliminary to further study.

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