Enhanced hepatocarcinogenicity by combined inhalation and oral exposures to N,N-dimethylformamide in male rats.
N,N-Dimethylformamide (DMF), a ubiquitous contaminant in living and working environments, enters the human body by inhalation, as well as by oral and dermal routes of exposure. In order to provide bioassay data for carcinogenic risk assessment of humans exposed to DMF by multiple routes of exposure, hepatocarcinogenic effect of combined inhalation and oral exposures of rats to DMF was examined. A group of 50 male F344 rats, 6-week-old, was exposed by inhalation to 0 (clean air), 200, or 400 ppm (v/v) of DMF vapor-containing air for 6 hr/day and 5 days/week during a 104-week period, and each inhalation group was given ad libitum DMF-formulated drinking water at 0, 800 or 1,600 ppm (w/w) for 104 weeks. Incidences of hepatocellular adenomas and carcinomas and their combined incidences were significantly increased in the combined-exposure groups compared with the untreated control group or each of the inhalation-alone and oral-alone groups with matching concentrations. Incidences of hepatocellular adenomas and carcinomas induced by the combined exposures were greater than the sum of the two incidences of the hepatocellular adenomas and carcinomas induced by the single-route exposures through inhalation and ingestion. The combined exposures enhanced tumor malignancy. It was concluded that the combined inhalation and oral exposures markedly enhance the incidences and malignancy of hepatocellular tumors, suggesting that the hepatocarcinogenic effect of the combined exposures is greater than the effect that would be expected under the assumption that the two effects of single-route exposures through inhalation and drinking are additive.
Ohbayashi
Hisao
H
Japan Bioassay Research Center, Japan Industrial Safety and Health Association, 24445 Hirasawa, Hadano, Kanagawa 257-0015, Japan. h-obayashi@jisha.or.jp
Umeda
Yumi
Y
Senoh
Hideki
H
Kasai
Tatsuya
T
Kano
Hirokazu
H
Nagano
Kasuke
K
Arito
Heihachiro
H
Fukushima
Shoji
S
D018248:Adenoma, Liver Cell / Q000139:chemically induced* / Q000401:mortality / Q000473:pathology; D000280:Administration, Inhalation; D000284:Administration, Oral; D000818:Animals; D001835:Body Weight; D002273:Carcinogens / Q000633:toxicity*; D006528:Carcinoma, Hepatocellular / Q000139:chemically induced* / Q000401:mortality / Q000473:pathology; D004126:Dimethylformamide; D004305:Dose-Response Relationship, Drug; D004326:Drinking; D004334:Drug Administration Schedule; D004785:Environmental Pollutants / Q000633:toxicity*; D005559:Formamides / Q000633:toxicity*; D019570:Inhalation Exposure; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344; D015996:Survival Rate; D013997:Time Factors; D014835:Volatilization; D014881:Water Supply
D002273:Carcinogens; D004785:Environmental Pollutants; D005559:Formamides; D004126:Dimethylformamide