and number of bacteria present; dietary nitrite intakes are much lower. It is possible that the development of physiologically based pharmacokinetic models for nitrate and nitrite metabolism and nitrosamine formation would allow each of those variables to be evaluated and the bounds on the dose-response relationships to be estimated (see Appendix A).


Studies in humans are inadequate to support an association between nitrate or nitrite exposure and reproductive or developmental effects. Therefore, developing dose-response relationships based on human data is not possible. Developmental effects and fetal toxicity have been reported among rats and mice receiving both nitrite and nitrosatable amines, but (as discussed above for cancer) developing dose-response relationships for humans on the basis of these data and estimating rates of nitrosamine formation and potency are so uncertain as to be meaningless.

Nitrate has not been reported to produce reproductive effects in animal bioassays. One study reported that nitrate produced alterations in rat neurobehavioral development at 7.5 mg/kg-day (Markel et al. 1989); although the study has several drawbacks, this is the lowest dosage at which any developmental effects have been reported. This dosage can be converted to a human adult dosage as follows:

(7.5 mg/kg-day)¾(70 kg) = 317 mg/day,

where the exponent ¾ is used to account for the difference in surface area between rats and humans (Federal Register 1992) and

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