Immunotoxicology: extrapolation from animal to man--estimation of the immunotoxicologic risk associated with TBTO exposure.
Bis(tri-n-butyltin)oxide (TBTO) has been shown to be immunotoxic in rodents, resulting in decreased resistance to infections. The no-effect level assessed by estimating effects on host resistance in rats has been found to lie between 0.5 and 5.0 mg TBTO/kg food (0.025 and 0.25 mg/kg body weight). For risk assessment such animal data need to be extrapolated to the human situation. In risk assessment procedures uncertainty factors are used to account for interspecies variation (extrapolation from animal to man) and for variation within the human species. For both factors a value of 10 is often used, based on international guidelines. Hence, exposures below 0.00025 mg/kg body weight should not pose a risk for the human population. In the present study we have taken an alternative approach. We have produced dose-response curves for the effect of TBTO exposure on resistance to Trichinella spiralis. To extrapolate this curve to the human situation, we produced additional dose response data concerning in vitro effects of TBTO exposure on the mitogen responsiveness of both rat lymphoid cells and human blood cells. Using regression analyses of these dose-response data, we calculated a factor that accounts for interspecies variation (IEV) and a factor that accounts for intraspecies variation (IAV) within the human samples. Using these factors, we estimated the dose that decreases resistance in man to an infection. We choose 10% increase of the infectious load as a reference point which in our view is of biological significance. Based on these considerations, we estimated the dose that may affect resistance in adult humans at 0.04 mg/kg body weight. Pre- and postnatal exposure will probably result in effects at lower concentrations, due to the vulnerability of the developing immune system.
Van Loveren
H
H
National Institute of Public Health and the Environment, Bilthoven, The Netherlands.
Slob
W
W
Vandebriel
R J
RJ
Hudspith
B N
BN
Meredith
C
C
Garssen
J
J
D000328:Adult; D000818:Animals; D005260:Female; D006801:Humans; D007154:Immune System Diseases / Q000139:chemically induced* / Q000150:complications; D007166:Immunosuppressive Agents / Q000009:adverse effects*; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D051381:Rats; D018570:Risk Assessment; D014220:Trialkyltin Compounds / Q000009:adverse effects*; D017160:Trichinella spiralis; D014235:Trichinellosis / Q000150:complications
D007166:Immunosuppressive Agents; D014220:Trialkyltin Compounds; C005961:bis(tri-n-butyltin)oxide