plasma half-life, or concentration at the receptor site could modify the dosage generated on a weight basis.

In chronic exposures, the differential rate of development of metabolizing enzymes such as glucuronyltransferase and the P-450-dependent mixed-function oxidases can have an impact on toxicity that is independent of overall metabolic rate. If the parent compound were the toxic substance, delayed enzymatic degradation would enhance toxicity. However, if a metabolite were the source of toxicity, the slower metabolism would result in reduced toxicity.

If the metabolism of a xenobiotic material is fully elucidated, it would be appropriate to use a reference base or denominator (weight, surface area, or metabolic rate) that best reflects the pharmacokinetics of that compound. When the developmental pharmacokinetics of a substance are not well delineated, as is often the case for pesticides, it has been demonstrated empirically that on a weight basis, the toxicity difference between immature and mature animals, based on comparative LD50s, is usually less than a factor of 5 and has only occasionally been reported to exceed a factor of 10 for any pesticide studied to date (Calabrese, 1986).

CONCLUSIONS AND RECOMMENDATIONS

Conclusions

In this chapter, the committee summarized the mechanisms of toxicity and explored the potentially vulnerable organ systems or functional systems in the developing animal. In addition, it reviewed data on toxicants that provide the basis for these conclusions. Although the committee was interested in drawing conclusions from toxicity testing of pesticides, in many cases there were no data on developing animals. To illustrate the principles of toxicity as they pertain to developing animals, the committee therefore utilized information from testing of other toxicants, including drugs.

As described in Chapter 2, the nervous system, the immune system, and reproductive systems continue to develop after birth. This observation heightens concern that toxicity during these postnatal developmental stages or periods may have lasting consequences throughout adult life.

  • Differences in toxicity between young and mature animals may be in either direction but are generally modest. The younger animal may be more sensitive or may be less sensitive than the older animal to comparable levels of exposure of toxic agents. The direction of these differences appears to be compound specific as well as age specific because toxicity may not vary linearly with age. In those instances where such measures



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