LEYDIG-CELL HYPERPLASIA AND ADENOMA FORMATION - MECHANISMS AND RELEVANCE TO HUMANS

Citation
Ed. Clegg et al., LEYDIG-CELL HYPERPLASIA AND ADENOMA FORMATION - MECHANISMS AND RELEVANCE TO HUMANS, Reproductive toxicology, 11(1), 1997, pp. 107-121
Citations number
170
Categorie Soggetti
Reproductive Biology",Toxicology
Journal title
ISSN journal
08906238
Volume
11
Issue
1
Year of publication
1997
Pages
107 - 121
Database
ISI
SICI code
0890-6238(1997)11:1<107:LHAAF->2.0.ZU;2-M
Abstract
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 .