THALIDOMIDE - LACK OF MUTAGENIC ACTIVITY ACROSS PHYLA AND GENETIC END-POINTS

The human and rabbit teratogen thalidomide has been tested for mutagen icity in a wide range of assays, ranging from bacterial gene mutation assays conducted in vitro to in vivo cytogenetic assays conducted usin g rabbits, and including a variety of human-derived tissues. Thalidomi de was not mutagenic to 6 strains of Salmonella when tested both in th e presence and absence of Aroclor-induced rat liver S9 mix. This inact ivity was confirmed in strains TA98 and TA100 using a 1-h pre-incubati on assay protocol with the same S9 mix (10% S9), and additionally, in strain TA98 using 3 concentrations of S9 (4%, 10% and 30% S9 in S9 mix ). Thalidomide was not clastogenic either to cultured human lymphocyte s (whole blood cultures, minus S9 mix) or to Chinese hamster ovary (CH O) cells treated in vitro, Further, no cytotoxicity was observed in pu rified human lymphocytes when exposed to thalidomide up to the limit o f its solubility in the medium in the presence and absence of liver S9 from Aroclor-induced pregnant rabbit. The CHO assays were conducted w ithout metabolic activation and in the presence of a variety of source s of auxiliary metabolic activation (PB/beta NP-induced rat liver S9 m ix, pooled male and female human liver S9 mix, uninduced and Aroclor-i nduced pregnant rabbit Liver S9 mix and foetal rabbit S9 mix). Thalido mide did not induce micronuclei in isolated human lymphocytes (minus S 9 mix) and it was non-mutagenic to mouse lymphoma L5178Y TK+/- cells w hen tested to the limits of its solubility in the culture medium (+/- S9 mix). No indication of recombinogenic or clastogenic activity was o bserved for thalidomide when tested in Drosophila. In addition, it fai led to induce chromosome aberrations in grasshopper neuroblasts when t ested in the presence and absence of Aroclor-induced rat liver S9 mix. Some unusual chromosome morphologies were observed in the grasshopper cytogenetic preparations indicating a potential of thalidomide to int eract with chromosomal proteins. However, this potential was not evide nt in the human lymphocyte micronucleus assay, and thalidomide was app arently not reactive to the proteins of the mouse skin, as it gave neg ative results in a mouse local lymph node assay for skin sensitizing a gents. Thalidomide was inactive in bone marrow micronucleus assays con ducted using males and females from two strains of mice, and female Ne w Zealand white rabbits. It is concluded that thalidomide is neither a mutagen nor an aneugen. This conclusion is discussed within the conte xt of the results of earlier mutagenicity studies, the recent claim th at thalidomide may be a heritable germ cell mutagen to humans, and the current interest in thalidomide for the treatment of immune system-re lated diseases. (C) 1997 Elsevier Science B.V.