A mechanism-based cancer risk assessment for 1,4-dichlorobenzene.
1,4-Dichlorobenzene (DCB) induced liver cancer in male and female B6C3F(1) mice in a gavage bioassay and in male and female BDF(1) mice in an inhalation bioassay. The weight of the evidence convincingly indicates that the mouse liver tumors induced by 1,4-DCB were via a nongenotoxic-mitogenic/promotional mode of action by forcing the growth of spontaneous precancerous lesions. Doses insufficient to exhibit mitogenic or promotional activity would not be expected to increase the risk of cancer. Benchmark dose modeling of the tumor response was conduced for the combined inhalation and oral gavage bioassay data sets based on an absorbed dose basis to establish the dose or airborne concentration corresponding to 1% extra risk. Assuming that as a point of departure and dividing by an uncertainty factor of 300, yielded a value of 0.1 ppm, representing a rational estimate of an airborne concentration for the human population below which there is unlikely to be any increased risk of cancer during a lifetime. In contrast, the default model that assumes a genotoxic mode of action estimates a one in one-million increased lifetime risk of cancer at an airborne concentration of 0.00004 ppm, some 2500-fold lower than the mechanism-based model and 1,875,000-fold lower than the no observed effect concentration for induced cancer of 75 ppm in the inhalation bioassay.
Butterworth
Byron E
BE
Butterworth Consulting, 4820 Regalwood Dr., Raleigh, NC 27613, USA. bebutterworth@earthlink.net
Aylward
Lesa L
LL
Hays
Sean M
SM
D000280:Administration, Inhalation; D000284:Administration, Oral; D000818:Animals; D019985:Benchmarking; D002273:Carcinogens / Q000633:toxicity*; D002722:Chlorobenzenes / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D019317:Evidence-Based Medicine; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D019570:Inhalation Exposure; D007306:Insecticides / Q000633:toxicity*; D008113:Liver Neoplasms / Q000139:chemically induced / Q000473:pathology; D008297:Male; D051379:Mice; D019055:No-Observed-Adverse-Effect Level; D051381:Rats; D018570:Risk Assessment; D014116:Toxicology / Q000379:methods*
D002273:Carcinogens; D002722:Chlorobenzenes; D007306:Insecticides; C018511:4-dichlorobenzene