Abstract
The teratogenic potency of the directly acting alkylating agent methylnitrosourea (MNU) was analysed in mice. Skeletal abnormalities were evaluated after treatment on either day 11 or 12 of pregnancy. Ectrodactyly was the predominant effect after treatment on day 11. Treatment on day 12 triggered especially double-sided microdactyly (method of analysis: measuring digit lengths). Litter variabilities were analysed using a new biometrical procedure. Using probit analysis, dose-response curves were computed from the experimental data obtained and the effective doses were calculated and compared with maternal toxicity. Low dose extrapolation was performed by use of various mathematical models which yielded very similar EDI/100 and EDI/1000 values.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Abbreviations
- DMN-OAc:
-
acetoxymethyl-methylnitrosamine
- EMS:
-
ethylmethanesulfonate
- MNU:
-
methylnitrosourea
References
Alexandrov VA (1973) Embryotoxic and teratogenic effects of chemical carcinogens. IARC Sci Publ 4: 112–126
Baß R, Günzel P, Henschler D, König J, Lorke D, Neubert D, Schütz E, Schuppan D, Zbinden G (1982) LD-50 versus acute toxicity. Critical assessment of the methodology currently in use. Arch Toxicol 51: 183–186
Beliles RP (1972) The influence of pregnancy on the acute toxicity of various compounds in mice. Toxicol Appl Pharmacol 23: 537–540
Bochert G, Rahm U, Schnieders B (1978) Pharmacokinetics of embryotoxic direct-acting alkylating agents: comparison of DNA alkylation of various maternal tissues and the embryo during organogenesis. In: Neubert D, Merker H-J, Nau H, Langman J (eds) Role of pharmacokinetics in prenatal and perinatal toxicology. G Thieme Publ, Stuttgart, pp 235–251
Bochert G, Platzek T, Wiessler M (1981) Comparison of effects on limb development in vivo and in vitro using methyl (acetoxymethyl) nitrosamine. In: Neubert D, Merker H-J (eds) Culture techniques. W de Gruyter, Berlin New York, pp 223–235
Bochert G, Platzek T, Blankenburg G, Wiessler M, Neubert D (1985) Embryotoxicity induced by alkylating agents: Leftsided preponderance of paw malformations induced by acetoxymethylmethylnitrosamine in mice. Arch Toxicol 56: 139–150
Bochert G, Platzek T, Neubert D (1987) DNA modification in murine embryos: a primary cause of embryotoxic effects. In: Nau H, Scott WJ (eds) Pharmacokinetics in teratogenesis, Vol II Experimental aspects in vivo and in vitro. CRC Press, Boca Raton Florida, pp 73–82
Brown NA, Fabro S (1983) The value of animal teratogenicity testing for predicting human risk. Clin Obstet Gynecol 26: 467–477
Brown NA, Shull G, Kao J, Goulding EH, Fabro S (1982) Teratogenicity and lethality of hydantoin derivatives in the mouse: structure-toxicity relationships. Toxicol Appl Pharmacol 64: 271–288
Chahoud I, Kwasigroch TE (1977) Controlled breeding of laboratory animals. In: Neubert D, Merker H-J, Kwasigroch TE (eds) Methods in prenatal toxicology. Thieme, Stuttgart, pp 78–91
Dawson AA (1926) A note on the staining of the skeleton of cleared specimen with alizarin red S. Stain Technol 1: 123–124
Fabro S, Shull G, Brown NA (1982) The relative teratogenic index and teratogenic potency: proposed components of developmental risk assessment. Teratogen Carcinogen Mutagen 2: 61–76
Garrett ER, Goto S, Stubbins JF (1965) Kinetics of solvolyses of various N-Alkyl-N-nitrosoureas in neutral and alkaline solutions. J Pharm Sci 54: 119–123
Gladen B (1979) The use of the Jackknife to estimate proportions from toxicological data in the presence of litter effects. J Am Statist Assoc 74: 278–283
Haseman JK, Kupper LL (1979) Analysis of dichotomous response data from certain toxicological experiments. Biometrics 35: 281–293
Koyama T, Handa J, Handa H, Matsumoto S (1970) Methy-lnitrosourea induced malformations. Arch Neurol 22: 342–347
von Kreybig T (1965) Die Wirkung einer carcinogenen Methylniroso Harnstoff-Dosis auf die Embryonalentwicklung der Ratte. Z Krebsforsch 67: 46–50
Krewski D, van Ryzin (1981) Dose-response models for quantal response toxicity data. In: Csorgo M, Dawson D, Rao JNK, Saleh E (eds) Statistics and related topics. North-Holland, New York, pp 201–231
Kupper LL, Haseman JK (1978) The use of a correlated binomial model for the analysis of certain toxicological experiments. Biometrics 34: 69–76
Kupper LL, Portier C, Hogan MD, Yamamoto E (1986) The impact of litter effects on dose-response modeling in teratology Biometrics 42: 85–98
Meister R (1987) Zur Analyse von Dosis-Wirkungs-Beziehungen in der Pränatal-Toxikologie, lecture held at the 32. Biometr. Colloquium of the German Section of the Internat. Biometr. Soc. in Ulm, FRG, Biometrics (in press)
Neubert D, Barrach HJ (1977) Organotropic effects and dose-response relationships in teratology. In: Neubert D, Merker H-J, Kwasigroch TE (eds) Methods in prenatal toxicology. Thieme, Stuttgart, pp 405–412
Neubert D, Chahoud I, Platzek T, Meister R (1987a) Principles and problems in assessing prenatal toxicity. Arch Toxicol 60: 238–245
Neubert D, Bochert G, Platzek T, Chahoud I, Fischer B, Meister R (1987b) Dose-response relationships in prenatal toxicity. Gongen Anom 27: 275–302
Platzek T, Bochert G, Schneider W, Neubert D (1982) Embryotoxicity induced by alkylating agents: 1. Ethylmethanesulfonate as a teratogen in mice — a model for dose-response relationships of alkylating agents. Arch Toxicol 51: 1–25
Platzek T, Bochert G, Rahm U (1983) Embryotoxicity induced by alkylating agents: teratogenicity of acetoxymethylmethylnitrosamine — dose-response relationship, application route dependency and phase specificity. Arch Toxicol 52: 45–69
Platzek T, Meister R, Bochert G, Pauli B (1986) Dose-response studies using methylnitrosourea: teratological, biometrical and biochemical aspects. Teratology 33: 26A
Platzek T, Meister R, Chahoud I, Bochert G, Krowke R, Neubert D (1987) Studies on mechanisms and dose-response relationships of prenatal toxicity. In: Welsch F (ed) Approaches to elucidate mechanisms in teratogenesis, Proceedings of the 8th CIIT Conference on Toxicology April 1986, Hemisphere Publ Corp Washington, New York, London pp 59–81
Scott WJ (1983) Caffeine-induced limb malformations: description of malformations and quantitation of placental transfer. Teratology 28: 427–435
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Platzek, T., Bochert, G., Pauli, B. et al. Embryotoxicity induced by alkylating agents: 5. Dose-response relationships of teratogenic effects of methylnitrosourea in mice. Arch Toxicol 62, 411–423 (1988). https://doi.org/10.1007/BF00288343
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00288343