In utero exposure to 1R4F reference cigarette smoke: evaluation of developmental toxicity.
The potential developmental effects of 1R4F reference cigarette smoke were examined using Sprague-Dawley rats exposed for 2 h/day, 7 days/week, by nose-only inhalation at target mainstream smoke concentrations of 150, 300, and 600 mg/m3 total particulate matter (TPM). Males were exposed 4 weeks prior to and during mating, with females exposed 2 weeks prior to mating and during mating, and through gestation day (GD) 20. Sham controls received filtered air to simulate nose-only exposure, while cage controls were maintained untreated. Smoke exposure was confirmed through biomarker evaluation (parental: carboxyhemoglobin, nicotine, and cotinine; fetal: nicotine and cotinine). Characteristic cigarette smoke-related histopathologic changes including nasal epithelial hyperplasia and squamous metaplasia and pigmented macrophages in the lung were observed in all exposed parental groups. Maternal toxicity during gestation was indicated at smoke concentrations of 300 and 600 mg TPM/m3, where corrected total body weight gain was significantly (p </= 0.05) decreased compared to sham controls. Food consumption was unaffected. Mating performance was unaffected by exposure: 71-75% pregnant in sham or cage control groups compared to 66-76% pregnant in smoke-exposed groups. Nicotine and cotinine were identified in the blood of fetuses from smoke-exposed dams on GD 20. Resorption rates, litter size, and sex ratio were equivalent among the groups. Fetal body weights at GD 20 were significantly reduced in the group exposed to 300 or 600 mg TPM/m3 compared to sham exposed controls. Developmental abnormalities were rare and sporadic in nature and the absence of a clear smoke concentration relationship suggested they were not related to cigarette smoke inhalation. Skeletal examinations revealed delayed ossification (supra occipital and sternebrae) in fetuses from dams exposed to 300 or 600 mg TPM/m3 smoke. High concentrations of 1R4F cigarette smoke were not teratogenic. The methodology used for this study was able to detect a decrease in fetal birthweight and this approach may be a useful tool for cigarette evaluation.
Carmines
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Philip Morris USA Research Center, 4201 Commerce Road, Richmond, Virginia 23261, USA. edward.l.carmines@pmusa.com
Gaworski
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Faqi
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Rajendran
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D000818:Animals; D000831:Animals, Newborn; D001835:Body Weight / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004435:Eating / Q000187:drug effects; D005314:Embryonic and Fetal Development / Q000187:drug effects; D005260:Female; D008297:Male; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D012098:Reproduction / Q000187:drug effects*; D012726:Sexual Behavior, Animal / Q000187:drug effects; D012907:Smoking / Q000009:adverse effects* / Q000473:pathology; D013997:Time Factors; D014026:Nicotiana / Q000633:toxicity*