Toxicology of Industrial Compounds

C.K.ATTERWILL AND S.P.AYLWARD 275
Conclusions
The observations now lend further and strong support to the hypothesis
that indirect xenobiotic-induced thyroid toxicology can arise from direct
effects on hepatic membrane-located thyroxine transport proteins. It also
suggests that the species-specificity of this toxic effect in vivo of some
xenobiotics may be attributed to actual species differences in the sensitivity
of these hepatic carriers to the compounds and not simply or primarily to
changes in T 4 glucuronidation via UDP-GT induction. For the first time we
have demonstrated the usefulness of Gunn rat hepatocytes in vitro for
discriminating between the two ‘hepatic subclasses’ of xenobiotics causing
thyroid toxicity in rodents.
A number of practical in vivo and in vitro investigative tests are now
available for delineating mechanisms of thyroid toxicity along the H-P-T-L
axis, and which also provide screening tools for examining chemical series
of potentially toxic molecules: (i) Direct block of thyroid function via
peroxidase inhibition can be measured in vivo by the perchlorate discharge
test (Atterwill et al., 1987); (ii) it can also be measured in vitro using
cultured thyrocytes (Atterwill and Fowler, 1990); (iii) indirect effects on
hepatic thyroxine clearance can be assessed in vivo (Atterwill et al., 1989);
or (iv) in vitro using cultured hepatocytes from different species or Gunn
rat (Aylward et al., 1994). Effects on receptors at the hypothalamic and
pituitary levels can also now be studied extensively using both in vivo and
in vitro approaches (Buckingham and Gillies, 1993). This battery of
technology now available will greatly advance the mechanistic
understanding and screening of thyroid endocrine toxicants.
References
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