EMBRYOTOXICITY INDUCED BY ALKYLATING-AGENTS .7. LOW-DOSE PRENATAL-TOXIC RISK-ESTIMATION BASED ON NOAEL RISK FACTOR APPROACH, DOSE-RESPONSE RELATIONSHIPS, AND DNA-ADDUCTS USING METHYLNITROSOUREA AS A MODEL-COMPOUND

Prenatal-toxic risk estimation for the alkylating model compound methy lnitrosourea (MNU) was performed using different procedures. Risk of l ow doses was estimated using linear extrapolation to zero (estimated E D0.1%: 0.1 mg/kg body wt MNU) as well as extrapolation by probit analy sis based on a dose-response study (estimated ED0.1%: 1.6 mg/kg body w t). Furthermore, a ''virtually safe dose'' was established by means of the NOAEL risk factor approach (e.g., factor 30: 0.03 mg MNU per kg b ody wt). In previous studies in murine embryos using MNU, we combined dose-response data and DNA adduct rate measurements and deduced that O 6-methylguanine is a suitable variable for molecular dosimetry. In a t entative approach, we estimated the teratogenic risk of low doses base d on the adduct rates of O6-methylguanine in the DNA of the embryos. I t is concluded that in the case of steep dose-response relationships, which are typical for the majority of teratogenic effects, the NOAEL r isk factor approach is more conservative than extrapolation based on p robit analysis. Risk estimation using dosimetry with this model compou nd yields estimated incidences similar to linear extrapolation.