Erratum: Retraction of the landmark glyphosate safety publication by Williams, Kroes and Munro (2000) should be reversed.
[This corrects the article on p. 1107 in vol. 25, PMID: 42517087.].
Published Erratum↗
Biomedical subjects
James E Klaunig
Publications and source records attributed to James E Klaunig.
Retraction of the landmark glyphosate safety publication by Williams, Kroes and Munro (2000) should be reversed.
The decision by the co-Editor-in-Chief of Regulatory Toxicology and Pharmacology, Prof. Martin van den Berg, to retract the 2000 review article by Williams, Kroes, and Munro has elicited widespread criticism within the scientific community. Issued in late 2025, the retraction decision cites procedural concerns including potential ghostwriting, undisclosed conflicts of interest, and omission of certain unpublished studies, invoking Committee on Publication Ethics guidelines despite lacking evidence of fraud or scientific flaws. This editorial argues that the retraction decision involves editorial overreach and misapplication of the guidelines. The alleged omissions stemmed from proprietary data access limitations that were disclosed in the original paper. Subsequent reviews by several independent expert panels and regulatory authorities with access to all glyphosate data, including the studies cited by the retracting editor, reached similar conclusions. Claims of ghostwriting were previously investigated and found lacking, including a declaration by EFSA as to the clarity of the conflict disclosures. The retraction's timing, reliance on litigation documents, and apparent biases that were not disclosed in the retraction notice raise questions of ideological interference. Absent substantive rebuttals based on scientific merit rather than speculative claims of inappropriate authorship and data access, this retraction decision sets a dangerous precedent for retroactive censorship, potentially chilling beneficial industry-academic collaborations and eroding trust in the integrity of scientific publishing. With the strongest conviction, we assert that retracting a paper without scientific flaws isn't protection-it is censorship. We therefore call for the immediate reversal of this flawed and unjustified retraction to preserve trust in peer-reviewed literature.
COPE↗
Role of the Kupffer cell in mediating hepatic toxicity and carcinogenesis.
Kupffer cells are resident macrophages of the liver and play an important role in its normal physiology and homeostasis as well as participating in the acute and chronic responses of the liver to toxic compounds. Activation of Kupffer cells directly or indirectly by toxic agents results in the release of an array of inflammatory mediators, growth factors, and reactive oxygen species. This activation appears to modulate acute hepatocyte injury as well as chronic liver responses including hepatic cancer. Understanding the role Kupffer cells play in these diverse responses is key to understanding mechanisms of liver injury. Idiosyncratic drug-induced liver disease results in morbidity and mortality, impacting severely on the development of new pharmacological agents. Modulation of the response of Kupffer cells by drugs has been suggested as a cause for the idiosyncratic response. Similarly, liver damage seen in chronic ethanol consumption appears to be modulated by Kupffer cell activation. More recent evidence has noted a contributory role of Kupffer cell activation in the process of hepatic carcinogenesis. Several nongenotoxic carcinogens, for example, activate Kupffer cells resulting in the release of cytokines and/or reactive oxygen species that induce hepatocyte cell proliferation and may enhance clonal expansion of preneoplastic cells leading to neoplasia. Kupffer cells therefore appear to play a central role in the hepatic response to toxic and carcinogenic agents. Taken together, the data presented in this symposium illustrate to the toxicologist the central role played by Kupffer cells in mediating hepatotoxicity.
Acute Disease↗
Mechanisms of 2-butoxyethanol-induced hemangiosarcomas.
Chronic exposure to 2-butoxyethanol increased liver hemangiosarcomas in male mice. The mechanism for the selective induction of hemangiosarcomas by 2-butoxyethanol is unknown but has been suggested to occur through non-DNA-reactive mechanisms. The occurrence of liver hemangiosarcomas in male mice has been linked to oxidative damage subsequent to RBC hemolysis and iron deposition and activation of macrophages (Kupffer cells) in the liver, events that exhibit a threshold in both animals and humans. 2-Butoxyethanol is metabolized to 2-butoxyacetaldehyde and 2-butoxyacetic acid, and although the aldehyde metabolite is short lived, the potential exists for this metabolite to cause DNA damage. The present study examined whether 2-butoxyethanol and its metabolites, 2-butoxyacetaldehyde and 2-butoxyacetic acid, damaged mouse endothelial cell DNA using the comet assay. No increase in DNA damage was observed following 2-butoxyethanol (1-10mM), 2-butoxyacetaldehyde (0.1-1.0mM), or 2-butoxyacetic acid (1-10mM) in endothelial cells after 2, 4, or 24 h of exposure. Additional studies examined the involvement of hemolysis and macrophage activation in 2-butoxyethanol carcinogenesis. DNA damage was produced by hemolyzed RBCs (10 x 10(6), 4 h), ferrous sulfate (0.1-1.0 microM; 2-24 h), and hydrogen peroxide (50-100 microM; 1-4 h) in endothelial cells. Hemolyzed RBCs also activated macrophages, as evidenced by increased tumor necrosis factor (TNF) alpha, while neither 2-butoxyethanol nor butoxyacetic acid increased TNF-alpha from macrophages. The effect of activated macrophages on endothelial cell DNA damage and DNA synthesis was also studied. Coculture of endothelial cells with activated macrophages increased endothelial cell DNA damage after 4 or 24 h and increased endothelial cell DNA synthesis after 24 h. These data demonstrate that 2-butoxyethanol and related metabolites do not directly cause DNA damage. Supportive evidence also demonstrated that damaged RBCs, iron, and/or products from macrophage activation (possibly reactive oxygen species) produce DNA damage in endothelial cells and that activated macrophages stimulate endothelial cell proliferation. These events coupled together provide the events necessary for the induction of hemangiosarcomas by 2-butoxyethanol.
Acetaldehyde↗
Acrylonitrile-induced oxidative DNA damage in rat astrocytes.
Chronic administration of acrylonitrile results in a dose-related increase in astrocytomas in rat brain, but the mechanism of acrylonitrile carcinogenicity is not fully understood. The potential of acrylonitrile or its metabolites to induce direct DNA damage as a mechanism for acrylonitrile carcinogenicity has been questioned, and recent studies indicate that the mechanism involves the induction of oxidative stress in rat brain. The present study examined the ability of acrylonitrile to induce DNA damage in the DI TNC1 rat astrocyte cell line using the alkaline Comet assay. Oxidized DNA damage also was evaluated using formamidopyrimidine DNA glycosylase treatment in the modified Comet assay. No increase in direct DNA damage was seen in astrocytes exposed to sublethal concentrations of acrylonitrile (0-1.0 mM) for 24 hr. However, acrylonitrile treatment resulted in a concentration-related increase in oxidative DNA damage after 24 hr. Antioxidant supplementation in the culture media (alpha-tocopherol, (-)-epigallocathechin-3 gallate, or trolox) reduced acrylonitrile-induced oxidative DNA damage. Depletion of glutathione using 0.1 mM DL-buthionine-[S,R]-sulfoximine increased acrylonitrile-induced oxidative DNA damage (22-46%), while cotreatment of acrylonitrile with 2.5 mM L-2-oxothiazolidine-4-carboxylic acid, a precursor for glutathione biosynthesis, significantly reduced acrylonitrile-induced oxidative DNA damage (7-47%). Cotreatment of acrylonitrile with 0.5 mM 1-aminobenzotriazole, a suicidal inhibitor of cytochrome P450, prevented the oxidative DNA damage produced by acrylonitrile. Cyanide (0.1-0.5 mM) increased oxidative DNA damage (44-160%) in astrocytes. These studies demonstrate that while acrylonitrile does not directly damage astrocyte DNA, it does increase oxidative DNA damage. The oxidative DNA damage following acrylonitrile exposure appears to arise mainly through the P450 metabolic pathway; moreover, glutathione depletion may contribute to the induction of oxidative DNA damage by acrylonitrile.
Acrylonitrile↗
Mode of action in relevance of rodent liver tumors to human cancer risk.
Hazard identification and risk assessment paradigms depend on the presumption of the similarity of rodents to humans, yet species specific responses, and the extrapolation of high-dose effects to low-dose exposures can affect the estimation of human risk from rodent data. As a consequence, a human relevance framework concept was developed by the International Programme on Chemical Safety (IPCS) and International Life Sciences Institute (ILSI) Risk Science Institute (RSI) with the central tenet being the identification of a mode of action (MOA). To perform a MOA analysis, the key biochemical, cellular, and molecular events need to first be established, and the temporal and dose-dependent concordance of each of the key events in the MOA can then be determined. The key events can be used to bridge species and dose for a given MOA. The next step in the MOA analysis is the assessment of biological plausibility for determining the relevance of the specified MOA in an animal model for human cancer risk based on kinetic and dynamic parameters. Using the framework approach, a MOA in animals could not be defined for metal overload. The MOA for phenobarbital (PB)-like P450 inducers was determined to be unlikely in humans after kinetic and dynamic factors were considered. In contrast, after these factors were considered with reference to estrogen, the conclusion was drawn that estrogen-induced tumors were plausible in humans. Finally, it was concluded that the induction of rodent liver tumors by porphyrogenic compounds followed a cytotoxic MOA, and that liver tumors formed as a result of sustained cytotoxicity and regenerative proliferation are considered relevant for evaluating human cancer risk if appropriate metabolism occurs in the animal models and in humans.
Animals↗
Species differences in the induction of hepatocellular DNA synthesis by diethanolamine.
Diethanolamine increased the incidence and multiplicity of liver tumors in the mouse following chronic exposure. Diethanolamine is known to inhibit cellular choline uptake. Since choline deficiency produces tumors in rodents, diethanolamine, through choline depletion, may result in tumor development in rodents. The potential for diethanolamine to function through this mode of action in humans is not known. The present studies examined the effect of diethanolamine (0-500 mug/ml) and choline depletion on DNA synthesis and changes in expression of genes involved in cell growth pathways in primary cultures of mouse, rat, and human hepatocytes. In mouse and rat hepatocytes DNA synthesis was increased following treatment with 10 mug/ml diethanolamine and higher (3- to 4-fold over control). In contrast, diethanolamine failed to increase DNA synthesis in human hepatocytes. Incubation of hepatocytes in medium containing reduced choline (1/10 to 1/100 of normal medium; 0.898 to 0.0898 mg/l vs. 8.98 mg/l) increased DNA synthesis (1.6- and 1.8-fold of control in mouse and rat hepatocytes, respectively); however, choline depletion did not induce DNA synthesis in human hepatocytes. Mouse and rat hepatocytes incubated in medium supplemented with 2- to 50-fold excess choline reduced diethanolamine-induced DNA synthesis to control levels or below. Gene expression analysis of mouse and rat hepatocytes following diethanolamine treatment showed increases in genes associated with cell growth and decreases in expression of genes involved in apoptotic pathways. These results support the hypothesis that choline depletion is central to the mode of action for the induction of rodent hepatic neoplasia by diethanolamine. Furthermore, since diethanolamine treatment or choline depletion failed to induce DNA synthesis in human hepatocytes, these results suggest that humans may not be at risk from the carcinogenic effects of diethanolamine.
Animals↗
Mechanisms of acrylamide induced rodent carcinogenesis.
Acrylamide is a monomer of polyacrylamide, used in biochemistry, in paper manufacture, in water treatment, and as a soil stabilizer. The monomer can cause several toxic effects and has the potential for human exposure either through the environment or from occupational exposure. Recently, additional concern for the potential toxicity of acrylamide in humans has arisen with the finding of acrylamide formation in some processed foods. It has been established that following chronic exposure, rats exhibited an increase in the incidence of adrenal pheochromocytomas, testicular mesotheliomas, thyroid adenomas and mammary neoplasms in F344 rats. This has raised increased concerns regarding the carcinogenic risk to humans from acrylamide exposure. Studies examining the DNA reactivity of acrylamide have been performed and have had differing results. The tissue and organ pattern of neoplastic development seen in the rat following acrylamide exposure is not consistent with that seen with other strictly DNA reactive carcinogens. Based on the pattern of neoplastic development, it appears that acrylamide is targeting endocrine sensitive tissues. In the current monograph, studies on the effect of acrylamide on DNA reactivity and on altered cell growth in the target tissues in the rat are reported. DNA synthesis was examined in F344 rats treated with acrylamide (0, 2, or 15 mg/kg/day) for 7, 14, or 28 days. Acrylamide increased DNA synthesis in the target tissues (thyroid, testicular mesothelium, adrenal medulla) at all doses and time points examined. In contrast, in a non-target tissue (liver), no increase in DNA synthesis was seen. Examination of DNA damage using single cell gel electrophoresis (the Comet assay) showed an increase in DNA damage in the target tissues, but not in non-target tissue (liver). In addition, a cellular transformation model, (the Syrian Hamster Embryo (SHE) cell morphological transformation model), was used to examine potential mechanisms for the observed carcinogenicity of acrylamide. SHE cell studies showed that glutathione (GSH) modulation by acrylamide was important in the cell transformation process. Treatment with a sulfhydryl donor compound (NAC) reduced acrylamide transformation while depletion of GSH (BSO) resulted in an enhancement of transformation. In summary, acrylamide caused both an increase in DNA synthesis and DNA damage in mammalian tissues and cells suggesting that DNA reactivity and cell proliferation, in concert, may contribute to the observed acrylamide-induced carcinogenicity in the rat and has implication on the possible risk for human neoplasm development.
Acrylamide↗
Indinavir impairs endothelial function in healthy HIV-negative men.
BACKGROUND: Potent antiretroviral treatment has drastically reduced mortality in HIV-infected patients but may accelerate atherosclerotic disease, which could be partially mediated via endothelial dysfunction. METHODS: In 8 HIV-negative healthy males, leg blood flow responses to intraartery infusions of methacholine chloride (Mch), sodium nitroprusside, and NG-mono-methyl-L-arginine (L-NMMA) were measured before and after 4 weeks of daily oral indinavir. In the same subjects, we also assessed the effect of indinavir on lipids, insulin sensitivity, markers of inflammation, as well as oxidative stress. RESULTS: After 4 weeks of indinavir, the endothelium-dependent response to methacholine chloride was impaired (195% +/- 38% vs 83% +/- 13%, P < .05), the response to NG-mono-methyl-L-arginine (nitric oxide-dependent tone) was nearly abrogated (-30% +/- 4% vs -1% +/- 11%, P < .05), whereas the endothelium-independent response to sodium nitroprusside remained unchanged. Fasting insulin levels increased from 5.8 +/- 1.2 to 7.0 +/- 1.4 microU/mL (P < .05), and HOMA-IR scores increased from 1.3 +/- 0.3 to 1.6 +/- 0.3 U (P < .05). There were no changes in blood pressure, lipids, markers of inflammation, or oxidative stress. CONCLUSIONS: Four weeks of the HIV-1 protease inhibitor indinavir, in the absence of HIV-1 infection, causes vascular dysfunction most likely at the level of endothelial nitric oxide production. The vascular dysfunction may be mediated partially by the concomitant induction of insulin resistance but other mechanisms cannot be ruled out.
Adult↗
Cancer biology and hormesis: commentary.
The observation of biphasic dose-response relationships following exposure to pharmacological and toxicological agents has been well documented. In this review Dr. Calabrese, using published data on human tumor cell lines treated with a variety of agents has provided additional support for the demonstration of hormesis in the cancer process. While this review has restricted the examination to human tumor cell lines, this limitation dose not take away from the value of the treatise and helps to point out the need for further analysis of the biphasic does response in other cancer models including in vivo carcinogenesis studies and human cancer epidemiology. This issue is further enhanced when the potential mechanisms for hormetic responses in the cancer cells are discussed, since the same mechanisms participate in the carcinogenesis process. Overall, this review provides an excellent opening examination into the definition of biphasic dose-response effects of toxic and pharmacological agents in cancer cells.
Adaptation, Physiological↗
Subchronic acrylamide treatment induces a tissue-specific increase in DNA synthesis in the rat.
Chronic treatment with acrylamide results in increased incidence of adrenal (pheochromocytoma), testicular (mesotheliomas) and thyroid (adenoma) neoplasia in male rats. While acrylamide has been demonstrated to be DNA reactive, the tissue pattern of neoplasm induction by acrylamide suggests other mechanisms in addition to DNA reactivity may be involved in the carcinogenesis of this compound. The present studies were performed to determine whether acrylamide or an acrylamide metabolite altered cell growth in the neoplastic target tissues in the rat. DNA synthesis, mitosis and apoptosis were examined in F344 and Sprague-Dawley male rats treated with acrylamide (0, 2, or 15 mg/kg/day) for 7, 14, or 28 days. Acrylamide increased DNA synthesis in the target tissues for tumor development (thyroid, testicular mesothelium, adrenal medulla) in both rat species. In contrast, cell growth was not altered in the liver and adrenal cortex (non-target tissues for acrylamide carcinogenesis). No changes in apoptosis or mitosis were observed in any of the tissues examined. Inhibition of oxidative metabolism of acrylamide using 1-aminobenzotriazole reduced acrylamide-induced DNA synthesis only in the adrenal medulla, having no apparent effect in the testicular mesolthelium or thyroid. In summary, acrylamide produced a selective increase in DNA synthesis that correlates with the previously reported tumor target tissues.
Acrylamide↗
The effects of ecstasy (MDMA) on rat liver bioenergetics.
OBJECTIVES: Use of the drug ecstasy (3,4-methylenedioxymethamphetamine [MDMA]) can result in life-threatening hyperthermia. Agents that uncouple mitochondrial oxidative phosphorylation are known to cause severe hyperthermia. In the present study, the authors tested the hypothesis that MDMA directly uncouples oxidative phosphorylation in rat liver mitochondria. METHODS: Effects on mitochondrial bioenergetics were assessed both in vitro and ex vivo. In vitro studies consisted of measuring the effects of MDMA (0.1-5.0 mmol/L) on states of respiration in isolated rat liver mitochondria and on mitochondrial membrane potential in a rat liver cell line. In ex vivo studies, mitochondrial rates of respiration were measured in the livers of rats one hour after treatment with MDMA (40 mg/kg subcutaneously). RESULTS: With the in vitro mitochondrial preparations, only concentrations of 5 mmol/L MDMA showed evidence of uncoupling with a slight increase in state 4 respiration and a corresponding decrease in the respiratory control index. MDMA (0.1-5.0 mmol/L) failed to decrease the mitochondrial membrane potential in 3,3-dihexyloxacarbocyanide iodide-stained WB-344 cells after either one or 24 hours of incubation. Ex vivo rates of respiration obtained from the livers of rats one hour after treatment with MDMA (40 mg/kg subcutaneously) showed no evidence of mitochondrial uncoupling. CONCLUSIONS: These data suggest that while high concentrations of MDMA have some mild uncoupling effects in isolated mitochondria, these effects do not translate to cell culture or ex vivo studies in treated animals. These data do not support the view that the hyperthermia induced by MDMA is from a direct effect on mitochondrial oxidative phosphorylation.
Animals↗
The role of oxidative stress in carcinogenesis.
Chemical carcinogenesis follows a multistep process involving both mutation and increased cell proliferation. Oxidative stress can occur through overproduction of reactive oxygen and nitrogen species through either endogenous or exogenous insults. Important to carcinogenesis, the unregulated or prolonged production of cellular oxidants has been linked to mutation (induced by oxidant-induced DNA damage), as well as modification of gene expression. In particular, signal transduction pathways, including AP-1 and NFkappaB, are known to be activated by reactive oxygen species, and they lead to the transcription of genes involved in cell growth regulatory pathways. This review examines the evidence of cellular oxidants' involvement in the carcinogenesis process, and focuses on the mechanisms for production, cellular damage produced, and the role of signaling cascades by reactive oxygen species.
Antioxidants↗
Effect of transport stress on respiratory disease, serum antioxidant status, and serum concentrations of lipid peroxidation biomarkers in beef cattle.
OBJECTIVE: To determine the effect of transportation stress on serum concentrations of oxidative stress biomarkers of calves. ANIMALS: 105 crossbred beef steer calves (mean [+/-SD] body weight, 207 +/- 21.2 kg). PROCEDURE: Calves were assembled at 1 location in Tennessee, and pretransit (day -3) blood samples were collected. Calves were allotted randomly by body weight into 2 groups. Calves were transported 1,930 miles to a feedlot in Texas, and 1 group received tilmicosin phosphate (33 microg/kg, s.c.) upon arrival. Calves were weighed and blood samples collected on the day of arrival (day 1) and on days 15, 22, and 28. Calves were scored daily for signs of bovine respiratory disease (BRD). Serum total antioxidant capacity (TACA) and serum malondialdehyde (MDA) concentrations were determined. RESULTS: Transportation stress significantly decreased mean serum TACA concentrations (from 147 +/- 31.2 U/mL to 133 +/- 20.1 U/mL) and significantly increased serum MDA concentrations (from 10.9 +/- 18.3 microg/mL to 30.2 +/- 50.5 microg/mL). Calves that died had a 43% increase in serum MDA concentration on day 1, compared with calves that lived (42.2 +/- 67.0 microg/mL vs 29.4 +/- 49.4 microg/mL, respectively). Calves that had > or =3 episodes of BRD had 2-fold higher serum MDA concentrations on day 1 than healthy calves. Tilmicosin-treated calves had a 20.8% significantly greater average daily gain and significantly greater serum TACA concentration than nontreated calves on day 28. CONCLUSIONS AND CLINICAL RELEVANCE: Transportation stress increases serum concentrations of oxidative stress biomarkers that are related to episodes of BRD and mortality in calves.
Animals↗
Minocycline blocks 6-hydroxydopamine-induced neurotoxicity and free radical production in rat cerebellar granule neurons.
Neurotoxicity induced by 6-hydroxydopamine (6-OHDA) is believed to be due, in part, to the production of reactive oxygen species (ROS). Anti-oxidants by inhibiting free radical generation, protect neurons against 6-OHDA-induced neurotoxicity. In this study, we investigated whether or not minocycline, a neuroprotective compound, could directly protect neurons against 6-OHDA-induced neurotoxicity and inhibit 6-OHDA-induced free radical production in cultured rat cerebellar granule neurons (CGN). We now report that exposure of CGN to 6-OHDA (100 microM) resulted in a significant increase in free radical production with death of 86% of CGN. Pretreatment with minocycline (10 microM) for 2 h prevented 6-OHDA-induced free radical generation and neurotoxicity. Furthermore, minocycline also attenuated H(2)O(2)-induced neurotoxicity. Our results suggest that minocycline blocks 6-OHDA-induced neuronal death possibly by inhibiting 6-OHDA-induced free radical generation in CGN. Both the antioxidative and neuroprotective effects of minocycline may be beneficial in the therapy of Parkinson's disease and other neurodegenerative diseases.
Adrenergic Agents↗
The human relevance of information on carcinogenic modes of action: overview.
Risk assessment policies and practice place increasing reliance on mode of action (MOA) data to inform conclusions about the human relevance of animal tumors. In June 2001, the Risk Science Institute of the International Life Sciences Institute formed a workgroup to study this issue. The workgroup divided into two subgroups, one developing and testing a "framework" for MOA relevance analysis and the other conducting an in-depth analysis of peroxisome proliferation-activated receptor (PPAR)alpha activation as the MOA for some animal carcinogens. This special issue of Critical Reviews in Toxicology presents the scientific reports emerging from this activity. These reports serve several purposes. For risk assessors in and out of government, they offer a new human relevance framework (HRF) that complements and extends existing guidance from other organizations. Regarding the specific MOA for peroxisome proliferating chemicals, these reports offer a state-of-the-science review of this important MOA and its role in tumorigenesis in three different tissues (liver, testis, and pancreas). The case studies in these reports present models for using MOA information to evaluate the hazard potential for humans. The cases also illustrate the substantial impact of a complete human relevance analysis, as distinct from an animal MOA analysis alone, on the nature and scope of risk assessment.
Animals↗
PPARalpha agonist-induced rodent tumors: modes of action and human relevance.
Widely varied chemicals--including certain herbicides, plasticizers, drugs, and natural products--induce peroxisome proliferation in rodent liver and other tissues. This phenomenon is characterized by increases in the volume density and fatty acid oxidation of these organelles, which contain hydrogen peroxide and fatty acid oxidation systems important in lipid metabolism. Research showing that some peroxisome proliferating chemicals are nongenotoxic animal carcinogens stimulated interest in developing mode of action (MOA) information to understand and explain the human relevance of animal tumors associated with these chemicals. Studies have demonstrated that a nuclear hormone receptor implicated in energy homeostasis, designated peroxisome proliferator-activated receptor alpha (PPARalpha), is an obligatory factor in peroxisome proliferation in rodent hepatocytes. This report provides an in-depth analysis of the state of the science on several topics critical to evaluating the relationship between the MOA for PPARalpha agonists and the human relevance of related animal tumors. Topics include a review of existing tumor bioassay data, data from animal and human sources relating to the MOA for PPARalpha agonists in several different tissues, and case studies on the potential human relevance of the animal MOA data. The summary of existing bioassay data discloses substantial species differences in response to peroxisome proliferators in vivo, with rodents more responsive than primates. Among the rat and mouse strains tested, both males and females develop tumors in response to exposure to a wide range of chemicals including DEHP and other phthalates, chlorinated paraffins, chlorinated solvents such as trichloroethylene and perchloroethylene, and certain pesticides and hypolipidemic pharmaceuticals. MOA data from three different rodent tissues--rat and mouse liver, rat pancreas, and rat testis--lead to several different postulated MOAs, some beginning with PPARalpha activation as a causal first step. For example, studies in rodent liver identified seven "key events," including three "causal events"--activation of PPARalpha, perturbation of cell proliferation and apoptosis, and selective clonal expansion--and a series of associative events involving peroxisome proliferation, hepatocyte oxidative stress, and Kupffer-cell-mediated events. Similar in-depth analysis for rat Leydig-cell tumors (LCTs) posits one MOA that begins with PPARalpha activation in the liver, but two possible pathways, one secondary to liver induction and the other direct inhibition of testicular testosterone biosynthesis. For this tumor, both proposed pathways involve changes in the metabolism and quantity of related hormones and hormone precursors. Key events in the postulated MOA for the third tumor type, pancreatic acinar-cell tumors (PACTs) in rats, also begin with PPARalpha activation in the liver, followed by changes in bile synthesis and composition. Using the new human relevance framework (HRF) (see companion article), case studies involving PPARalpha-related tumors in each of these three tissues produced a range of outcomes, depending partly on the quality and quantity of MOA data available from laboratory animals and related information from human data sources.
Animals↗
Comparative effects of phthalate monoesters on gap junctional intercellular communication and peroxisome proliferation in rodent and primate hepatocytes.
Several phthalate esters, compounds used as plasticizers in a variety of commercial products, have been shown to induce hepatic tumors in rodents. In this study, the comparative effects of phthalate monoesters on inhibition of gap junctional intercellular communication and induction of peroxisomal beta-oxidation were assessed in primary cultured hepatocytes from rats, mice, hamsters, cynomolgus monkeys, and humans. A human liver cell line was also utilized. Eight monoesters examined included mono-2-ethylhexyl phthalate (MEHP), mono-n-octyl phthalate (MNOP), mono-isononyl phthalate (MINP, 3 types, -1, -2, and -3), mono-isoheptyl phthalate (MIHP), mono-isodecyl phthalate (MIDP), and mono-(heptyl, nonyl, undecyl) phthalate (M711P). Gap junctional intercellular communication was measured 4 and 24 h after treatment by lucifer yellow dye coupling. Gap junctional intercellular communication was inhibited in rat and mouse hepatocytes by all eight monoesters in a concentration-dependent manner. In most cases, gap junctional intercellular communication was significantly reduced at the lowest concentrations tested (50 pM). Inhibition of gap junctional intercellular communication in rodent cells was substantially reversed within 24 h of monoester removal. In contrast, cell-to-cell communication was not inhibited in hamster, cynomolgus, or human hepatocytes or in a human liver cell line at any concentration examined. In rat hepatocytes, peroxisomal beta-oxidation was elevated after treatment with MEHP, MINP, MIHP, and MIDP but not MNOP or M711P, and with all but MIHP in mouse hepatocytes. The eight phthalates produced no marked change on peroxisomal beta-oxidation in hepatocytes from other species. These data provide additional evidence that the toxicological effects of phthalate esters are species specific.
Adult↗