Induced regenerative cell proliferation in livers and kidneys of male F-344 rats given chloroform in corn oil by gavage or ad libitum in drinking water

Constructing Scientific Authorities: Issue Framing of Chlorinated Disinfection Byproducts in Public Health

“…Toxicology research was initially focused on chloroform and its mode of action, particularly in the United States where the U.S. EPA set nonlegally enforceable Maximum Contaminant Level Goals for chloroform in drinking water. The International Life Sciences Institute, representing scientists from government, academia, and industry, conducted an expert panel assessment of chloroform and dichloroacetic acid and concluded that chloroform is safe at low doses (ILSI, 1997), drawing on studies (e.g., Larson, Sprankle, & Butterworth, 1994; Larson, Wolf, & Butterworth, 1994b, 1995; Larson et al , 1995; Templin et al , 1996) that demonstrated that liver tumors are a secondary occurrence to cell proliferation and death.…”

Constructing Scientific Authorities: Issue Framing of Chlorinated Disinfection Byproducts in Public Health

“…Toxicology research was initially focused on chloroform and its mode of action, particularly in the United States where the U.S. EPA set nonlegally enforceable Maximum Contaminant Level Goals for chloroform in drinking water. The International Life Sciences Institute, representing scientists from government, academia, and industry, conducted an expert panel assessment of chloroform and dichloroacetic acid and concluded that chloroform is safe at low doses (ILSI, 1997), drawing on studies (e.g., Larson, Sprankle, & Butterworth, 1994; Larson, Wolf, & Butterworth, 1994b, 1995; Larson et al , 1995; Templin et al , 1996) that demonstrated that liver tumors are a secondary occurrence to cell proliferation and death.…”

Risk Assessment of Inhaled Chloroform Based on Its Mode of Action

“…Initial work revolved around understanding route-specific differences in target tissue response. In general, exposure by the drinking water route failed to produce short-term evidence of toxicity, whereas exposure by inhalation or via corn-oil gavage routinely caused dosedependent target organ toxicity (14,(17)(18)(19)(20)(21). Female B6C3F, mice given chloroform either by cornoil gavage or through the drinking water developed routespecific patterns of hepatotoxicity and hepatocyte proliferation that correlated well with the hepatic tumor outcome (17).…”

Re-evaluation of the 2-Year Chloroform Drinking Water Carcinogenicity Bioassay in Osborne-Mendel Rats Supports Chronic Renal Tubule Injury as the Mode of Action Underlying the Renal Tumor Response

“…On average, tumors associated with the gavage mode of administration were at least twice the size of those produced by chloroform in drinking water. Such tumor size disparity can be matched with the differences recorded in the extent of hepatic and renal toxicity and cell proliferation induced by the two different modes of administration (Larson et al, 1995a;Pereira, 1994), gavage exposure producing the more severe toxic response in each organ. Once-daily bolus delivery of chloroform is thought to result in higher target tissue levels than occurs following exposure to the same total dose consumed via the drinking water in fractionated quantities spread over a 24-h period.…”

“…Moreover, this represents the first report identifying the constellation of changes described (focal nuclear crowding without thickened basement membranes but with basophilia, nucleolar hypertrophy, and apparent obscuring of the tubule lumen) as a histologic marker of chronically sustained, simple renal tubule hyperplasia. Cytoplasmic vacuolation as a manifestation of toxic injury was also seen in proximal convoluted tubules in studies examining the acute and subacute effects of chloroform in rats (Larson et al, 1995a;Templin et al, 1996b). Nuclear crowding reflects a local increase in cell number consistent with simple tubule hyperplasia (Hard et al, 1995).…”

Constructing Scientific Authorities: Issue Framing of Chlorinated Disinfection Byproducts in Public Health

“…Toxicology research was initially focused on chloroform and its mode of action, particularly in the United States where the U.S. EPA set nonlegally enforceable Maximum Contaminant Level Goals for chloroform in drinking water. The International Life Sciences Institute, representing scientists from government, academia, and industry, conducted an expert panel assessment of chloroform and dichloroacetic acid and concluded that chloroform is safe at low doses (ILSI, 1997), drawing on studies (e.g., Larson, Sprankle, & Butterworth, 1994; Larson, Wolf, & Butterworth, 1994b, 1995; Larson et al , 1995; Templin et al , 1996) that demonstrated that liver tumors are a secondary occurrence to cell proliferation and death.…”

Risk Assessment of Inhaled Chloroform Based on Its Mode of Action

“…Initial work revolved around understanding route-specific differences in target tissue response. In general, exposure by the drinking water route failed to produce short-term evidence of toxicity, whereas exposure by inhalation or via corn-oil gavage routinely caused dosedependent target organ toxicity (14,(17)(18)(19)(20)(21). Female B6C3F, mice given chloroform either by cornoil gavage or through the drinking water developed routespecific patterns of hepatotoxicity and hepatocyte proliferation that correlated well with the hepatic tumor outcome (17).…”

Re-evaluation of the 2-Year Chloroform Drinking Water Carcinogenicity Bioassay in Osborne-Mendel Rats Supports Chronic Renal Tubule Injury as the Mode of Action Underlying the Renal Tumor Response

“…On average, tumors associated with the gavage mode of administration were at least twice the size of those produced by chloroform in drinking water. Such tumor size disparity can be matched with the differences recorded in the extent of hepatic and renal toxicity and cell proliferation induced by the two different modes of administration (Larson et al, 1995a;Pereira, 1994), gavage exposure producing the more severe toxic response in each organ. Once-daily bolus delivery of chloroform is thought to result in higher target tissue levels than occurs following exposure to the same total dose consumed via the drinking water in fractionated quantities spread over a 24-h period.…”

“…Moreover, this represents the first report identifying the constellation of changes described (focal nuclear crowding without thickened basement membranes but with basophilia, nucleolar hypertrophy, and apparent obscuring of the tubule lumen) as a histologic marker of chronically sustained, simple renal tubule hyperplasia. Cytoplasmic vacuolation as a manifestation of toxic injury was also seen in proximal convoluted tubules in studies examining the acute and subacute effects of chloroform in rats (Larson et al, 1995a;Templin et al, 1996b). Nuclear crowding reflects a local increase in cell number consistent with simple tubule hyperplasia (Hard et al, 1995).…”

Constructing Scientific Authorities: Issue Framing of Chlorinated Disinfection Byproducts in Public Health

“…Toxicology research was initially focused on chloroform and its mode of action, particularly in the United States where the U.S. EPA set nonlegally enforceable Maximum Contaminant Level Goals for chloroform in drinking water. The International Life Sciences Institute, representing scientists from government, academia, and industry, conducted an expert panel assessment of chloroform and dichloroacetic acid and concluded that chloroform is safe at low doses (ILSI, 1997), drawing on studies (e.g., Larson, Sprankle, & Butterworth, 1994; Larson, Wolf, & Butterworth, 1994b, 1995; Larson et al , 1995; Templin et al , 1996) that demonstrated that liver tumors are a secondary occurrence to cell proliferation and death.…”

Risk Assessment of Inhaled Chloroform Based on Its Mode of Action

“…Initial work revolved around understanding route-specific differences in target tissue response. In general, exposure by the drinking water route failed to produce short-term evidence of toxicity, whereas exposure by inhalation or via corn-oil gavage routinely caused dosedependent target organ toxicity (14,(17)(18)(19)(20)(21). Female B6C3F, mice given chloroform either by cornoil gavage or through the drinking water developed routespecific patterns of hepatotoxicity and hepatocyte proliferation that correlated well with the hepatic tumor outcome (17).…”

Re-evaluation of the 2-Year Chloroform Drinking Water Carcinogenicity Bioassay in Osborne-Mendel Rats Supports Chronic Renal Tubule Injury as the Mode of Action Underlying the Renal Tumor Response

“…On average, tumors associated with the gavage mode of administration were at least twice the size of those produced by chloroform in drinking water. Such tumor size disparity can be matched with the differences recorded in the extent of hepatic and renal toxicity and cell proliferation induced by the two different modes of administration (Larson et al, 1995a;Pereira, 1994), gavage exposure producing the more severe toxic response in each organ. Once-daily bolus delivery of chloroform is thought to result in higher target tissue levels than occurs following exposure to the same total dose consumed via the drinking water in fractionated quantities spread over a 24-h period.…”

“…Moreover, this represents the first report identifying the constellation of changes described (focal nuclear crowding without thickened basement membranes but with basophilia, nucleolar hypertrophy, and apparent obscuring of the tubule lumen) as a histologic marker of chronically sustained, simple renal tubule hyperplasia. Cytoplasmic vacuolation as a manifestation of toxic injury was also seen in proximal convoluted tubules in studies examining the acute and subacute effects of chloroform in rats (Larson et al, 1995a;Templin et al, 1996b). Nuclear crowding reflects a local increase in cell number consistent with simple tubule hyperplasia (Hard et al, 1995).…”