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

Abstract

Prenatal-toxic risk estimation for the alkylating model compound methylnitrosourea (MNU) was performed using different procedures. Risk of low doses was estimated using linear extrapolation to zero (estimated ED0.1%: 0.1 mg/kg body wt MNU) as well as extrapolation by probit analysis based on a dose-response study (estimated ED0.1%: 1.6 mg/kg body wt). 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 body wt). In previous studies in murine embryos using MNU, we combined dose-response data and DNA adduct rate measurements and deduced that O6-methylguanine is a suitable variable for molecular dosimetry. In a tentative approach, we estimated the teratogenic risk of low doses based on the adduct rates of O6-methylguanine in the DNA of the embryos. It is concluded that in the case of steep dose-response relationships, which are typical for the majority of teratogenic effects, the NOAEL risk factor approach is more conservative than extrapolation based on probit analysis. Risk estimation using dosimetry with this model compound yields estimated incidences similar to linear extrapolation.

DNA alkylation studies of combined treatment with methylnitrosourea and ethylmethanesulfonate in mice

“…In the case of MNU and EMS, the functions of the adduct rate O 6 -alkylguanine related to the dose were previously determined as follows [6,7] Corresponding to Eq. I, an MNU dose of 2.1 mg/kg would trigger an alkylation rate of 1.3 pmol, whereas a dose of 100 mg/kg EMS would lead to an alkylation rate of 1.9 pmol corresponding to Eq.…”

“…Additionally, the for-mation of methylated and ethylated DNA adducts in 11-day-old embryos was determined by investigating these agents: DMN-OAc [4], MNU [5], and EMS [6]. Against this background, the low-dose prenatal toxic risk was estimated using various approaches including molecular dosimetry [7,8].…”

Embryotoxicity induced by alkylating agents: 6. DNA adduct formation induced by methylnitrosourea in mouse embryos

“…Data on DNA adduct rates at close levels well below the teratogenic dose range may allow attempts for a risk assessment of low doses based on DNA adduct rates. Such evaluations of the data which have been presented here on MNU have been initiated and some preliminary results have been published (MNU: Platzek et al 1989;EMS: Platzek and Bochert 1990).…”

Embryotoxicity induced by alkylating agents: 9. Low dose prenatal‐toxic risk estimation of ethylmethanesulfonate based on No‐observed‐adverse‐effect‐level risk factor approach, dose‐response relationships, and molecular dosimetry

“…Risk means the probability of an adverse effect induced by a certain dose of a drug or xenobiotic [I]. In this regard an exposure level shall be determined associated with no or an acceptable low risk or a dose is to be defined where an adverse effect with a certain incidence is likely to occur [2].…”

“…In a recent publication we considered prenatal-toxic risk estimation for the methylating agent methylnitrosourea (MNU) [2]. In a comparative way the risk of low doses was estimated using linear extrapolation as well as extrapolation by probit analysis.…”