Ed. Clegg et al., LEYDIG-CELL HYPERPLASIA AND ADENOMA FORMATION - MECHANISMS AND RELEVANCE TO HUMANS, Reproductive toxicology, 11(1), 1997, pp. 107-121
Leydig cell adenomas are observed frequently in studies evaluating the
chronic toxicity of chemical agents in laboratory animals, Doubts hav
e been raised about the relevance of such responses for human risk ass
essment, but the question of relevance has not been evaluated and pres
ented in a comprehensive manner by a broad group of experts, This arti
cle reports the consensus conclusions from a workshop on rodent Leydig
cell adenomas and human relevance. Five aspects of Leydig cell biolog
y and toxicology were discussed: 1) control of Leydig cell proliferati
on; 2) mechanisms of toxicant-induced Leydig cell hyperplasia and tumo
rigenesis; 3) pathology of Leydig cell adenomas; 4) epidemiology of Le
ydig cell adenomas; and 5) risk assessment for Leydig cell tumorigens.
Important research needs also were identified, Uncertainty exists abo
ut the true incidence of Leydig cell adenomas in men, although apparen
t incidence is rare and restricted primarily to white males, Also, sur
veillance databases for specific therapeutic agents as well as nicotin
e and lactose that have induced Leydig cell hyperplasia or adenoma in
test species have detected no increased incidence in humans, Because u
ncertainties exist about the true incidence in humans, induction of Le
ydig cell adenomas in test species may be of concern under some condit
ions, Occurrence of Leydig cell hyperplasia alone in test species afte
r lifetime exposure to a chemical does not constitute a cause for conc
ern in a risk assessment for carcinogenic potential, but early occurre
nce may indicate a need for additional testing, Occurrence of Leydig c
ell adenomas in test species is of potential concern as both a carcino
genic and reproductive effect if the mode of induction and potential e
xposures cannot be ruled out as relevant for humans, The workgroup foc
used on seven hormonal modes of induction of which two, GnRH agonism a
nd dopamine agonism, were considered not relevant to humans, Androgen
receptor antagonism, 5 alpha-reductase inhibition, testosterone biosyn
thesis inhibition, aromatase inhibition, and estrogen agonism were con
sidered to he relevant or potentially relevant, but quantitative diffe
rences may exist across species, with rodents being more sensitive, A
margin of exposure (MOE; the ratio of the lowest exposure associated w
ith toxicity to the human exposure level) approach should be used for
compounds causing Leydig cell adenoma by a hormonal mode that is relev
ant to humans. For agents that are positive for mutagenicity, the deci
sion regarding a MOE or linear extrapolation approach should be made o
n a case-by-case basis, In the absence of information about mode of in
duction, it is necessary to utilize default assumptions, including lin
ear behavior below the observable range, All of the evidence should be
weighed in the decision-making process. (C) 1997 Elsevier Science Inc
.