Route of chemical delivery and amount delivered to site of action matters in deciding chemical toxicity

Route of chemical delivery and amount delivered to site of action matters in deciding the degree of toxicity of a chemical. We know that direct injection of either caffeine (or herbicides) into embryos can easily damage the embryo, but humans can safely drink caffeine in moderation.

Takashi Kobayashi, Atsuyuki Nishida, Akane Kurokawa, and Fumio Ariyuki
(1995) Cardiovascular Malformations Induced by Caffeine and Phenobarbital in Chick Embryos AATEX 3. 17-27

The usage of chick embryos for studying the mechanism of cardiovascular malformations caused by chemicals was studied. Caffeine, well known as a teratogen for the cardiovascular system of chick embryos, was administered at the dose of 3.0 mg per egg to chick embryos from two different breeds between incubation day 2 (ID2, Hamburger and Hamilton stage 14) and 5 (Hamburger and Hamilton stage 27). The eggs were incubated until ID12 to examine the cardiovascular malformation. Treatment at Hamburger and Hamilton stage 19 (ID3) was highly lethal and treatment at this stage and at stages 23-24 (ID4) induced a high degree of cardiovascular malformation in the embryos from both breeds. The embryotoxicity caused by caffeine in the two different breeds similarly varied with the developmental stage of treatment.

Paganelli, A., Gnazzo, V., Acosta, H., López, S.L., Carrasco, A.E. 2010. Glyphosate-based herbicides produce teratogenic effects on vertebrates by impairing retinoic acid signalling. Chem. Res. Toxicol., August 9.

The broad spectrum herbicide glyphosate is widely used in agriculture worldwide. There has been ongoing controversy regarding the possible adverse effects of glyphosate on the environment and on human health. Reports of neural defects and craniofacial malformations from regions where glyphosate-based herbicides (GBH) are used led us to undertake an embryological approach to explore the effects of low doses of glyphosate in development. Xenopus laevis embryos were incubated with 1/5000 dilutions of a commercial GBH. The treated embryos were highly abnormal with marked alterations in cephalic and neural crest development and shortening of the anterior−posterior (A-P) axis. Alterations on neural crest markers were later correlated with deformities in the cranial cartilages at tadpole stages. Embryos injected with pure glyphosate showed very similar phenotypes. Moreover, GBH produced similar effects in chicken embryos, showing a gradual loss of rhombomere domains, reduction of the optic vesicles, and microcephaly. This suggests that glyphosate itself was responsible for the phenotypes observed, rather than a surfactant or other component of the commercial formulation. A reporter gene assay revealed that GBH treatment increased endogenous retinoic acid (RA) activity in Xenopus embryos and cotreatment with a RA antagonist rescued the teratogenic effects of the GBH. Therefore, we conclude that the phenotypes produced by GBH are mainly a consequence of the increase of endogenous retinoid activity. This is consistent with the decrease of Sonic hedgehog (Shh) signaling from the embryonic dorsal midline, with the inhibition of otx2 expression and with the disruption of cephalic neural crest development. The direct effect of glyphosate on early mechanisms of morphogenesis in vertebrate embryos opens concerns about the clinical findings from human offspring in populations exposed to GBH in agricultural fields.

( See a discussion of Paganelli et al at Biofortified Forum)

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