Narotsky M G, Weller E A, Chinchilli V M, Kavlock R J
ManTech Environmental Technology, Inc. Research Triangle Park, North Carolina 27709, USA.
Fundam Appl Toxicol. 1995 Sep;27(2):203-16. doi: 10.1006/faat.1995.1125.
In order to identify nonadditive effects on development, three compounds were combined using five dosages of each agent (a 5 x 5 x 5 full-bacterial design). Trichloroethylene (TCE), di(2-ethylhexyl) phthalate (DEHP), and heptachlor (HEPT), in corn oil, were administered by gavage to Fischer-344 rats on Gestation Days 6-15. Dose levels were 0, 10.1, 32, 101, and 320 mg/kg/day for TCE; 0, 24.7, 78, 247, and 780 mg/kg/day for DEHP; and 0, 0.25, 0.8, 2.5, and 8 mg/kg/day for HEPT. The dams were allowed to deliver and their pups were weighed and examined postnatally. Maternal death showed no main effects but DEHP and HEPT were synergistic. For maternal weight gain on Gestational Days 6-8, main effects for all three agents were observed, as well as 6-8 main effects for all three agents were observed, as well as TCE-DEHP synergism, and DEHP-HEPT antagonism. Maternal weight gain on Gestational Days 6-20 adjusted for litter weight showed main effects for TCE and HEPT, but no interactions. Main effects for all three agents were evident for full-litter resorptions and prenatal loss. The HEPT main effects were unexpected and were interpreted as reflecting potentiation by HEPT of the other agents. For full-litter loss, the TCE-HEPT and DEHP-HEPT interactions were antagonistic, perhaps due to a "ceiling" effect. For prenatal loss, the TCE-DEHP interaction was synergistic. Postnatal loss showed DEHP and HEPT main effects but no interaction. Analysis of pup weights on Day 1 revealed TCE and DEHP main effects and DEHP-HEPT antagonism; on Day 6, DEHP and HEPT main effects, DEHP-HEPT antagonism, and TCE-DEHP synergism were evident. Microphthalmia and anophthalmia incidences revealed TCE and DEHP main effects but no interactions. This extensive examination of a full-factorial design elucidates the complexities of studying and interpreting mixture toxicity. The data are available for further analysis.
为了确定对发育的非加性效应，使用每种药剂的五种剂量组合了三种化合物（5×5×5全因子设计）。将玉米油中的三氯乙烯（TCE）、邻苯二甲酸二（2-乙基己基）酯（DEHP）和七氯（HEPT）在妊娠第6至15天通过灌胃给予Fischer-344大鼠。TCE的剂量水平为0、10.1、32、101和320毫克/千克/天；DEHP的剂量水平为0、24.7、78、247和780毫克/千克/天；HEPT的剂量水平为0、0.25、0.8、2.5和8毫克/千克/天。让母鼠分娩，并在产后对其幼崽进行称重和检查。母体死亡未显示主要效应，但DEHP和HEPT具有协同作用。对于妊娠第6至8天的母体体重增加，观察到所有三种药剂的主要效应，以及TCE-DEHP协同作用和DEHP-HEPT拮抗作用。根据窝仔体重调整后的妊娠第6至20天的母体体重增加显示出TCE和HEPT的主要效应，但无相互作用。所有三种药剂对全窝吸收和产前损失均有明显的主要效应。HEPT的主要效应出乎意料，被解释为反映了HEPT对其他药剂的增强作用。对于全窝损失，TCE-HEPT和DEHP-HEPT相互作用具有拮抗作用，可能是由于“天花板”效应。对于产前损失，TCE-DEHP相互作用具有协同作用。产后损失显示DEHP和HEPT的主要效应，但无相互作用。对第1天幼崽体重的分析显示TCE和DEHP的主要效应以及DEHP-HEPT拮抗作用；在第6天，DEHP和HEPT的主要效应、DEHP-HEPT拮抗作用以及TCE-DEHP协同作用明显。小眼症和无眼症发生率显示TCE和DEHP的主要效应，但无相互作用。对全因子设计的这种广泛检查阐明了研究和解释混合物毒性的复杂性。数据可供进一步分析。
