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PubMed2002

Incorporating mechanistic data into risk assessment.

Incorporating mechanistic data into risk assessment is intended to improve the overall scientific validity, and thereby reduce the uncertainty, in human risk analysis. Relevant mechanistic data provides a link between the molecular and cellular event(s) and adverse outcome, and insight into mechanism of action is critical for accurate evaluation of dose-response relationships and inter-species extrapolation. This paper provides an example of applying mechanistic data to human risk assessment using the frameworks outlined by the International Programme on Chemical Safety (IPCS) and the U.S. Environmental Protection Agency (USEPA). Key components of the data are used to address the strength and consistency of the mechanism and to apply these data to human risk characterization.

Animals↗
PubMed1999

Chronic toxicity and carcinogenicity testing in the Sprague-Dawley rat of a prospective insect repellant (KBR 3023) using the dermal route of exposure.

The chronic toxicology and carcinogenic potential of 1-(1-methyl-propoxycarbonyl)-2-(2-hydroxyethyl)-piperidine (KBR 3023), a prospective new insect repellent intended for human use, was studied in rats using the dermal route of application. Relying upon the toxicology profile that emerged in the subchronic rat bioassay that was conducted using dermally applied dosages of 0, 80, 200, 500 and 1000 mg KBR 3023/kg body wt/day, it was determined, in concert with the Environmental Protection Agency (EPA), that dermally applied dosages of 0, 50, 100 or 200 mg KBR 3023/kg body wt/day would be used in the conduction of all definitive forms of subchronic, chronic, and lifetime descriptive testing performed with the chemical. Using this testing approach, the specific results of this 2-year study are as follows. All in-life parameters, which included body weight, food consumption, clinical observations, survival, ophthalmology, clinical chemistry, hematology, and urinalysis, were unaffected by exposure to KBR 3023. Similarly, postmortem analyses, which included organ weights and gross pathology, were also unchanged following exposure to KBR 3023. Histopathology at the dose site/skin was characterized by a pattern of acanthosis and/or hyperkeratosis across all doses in 1- and 2-year rats. Beyond the dosing site, cystic degeneration of the liver was described in 2-year 200-mg KBR 3023/kg body wt/day males. No other compound-related non-dosing site lesion was identified at any dose tested. No evidence of a compound-induced neoplasia was suggested in this bioassay.

Administration, Cutaneous↗
PubMed2000

Selection of protective action guides for nuclear incidents. EPA.

In 1991 the Environmental Protection Agency (EPA) published its revised Manual of Protective Action Guides and Protective Actions for Nuclear Incidents. The protective action guides contained in the manual represent EPA's formal recommendations to Federal, State, and local emergency response officials for protecting public health and safety during a nuclear incident. These guides are expressed in terms of the projected dose at which action(s) should be taken to reduce or eliminate that dose. In determining the appropriate values for the protective action guides, the Agency considered the following four principles: (1) acute health effects should be avoided, (2) the risk of delayed health effects should be minimized, (3) the values should not be higher than justified by a cost-benefit analysis, and (4) the risk to health from implementing the protective action should not be greater than the risk from the dose avoided. This paper examines each of these principles and their application in the selection of the evacuation and sheltering protective action guides for the early, or immediate, phase of a nuclear incident.

Disaster Planning↗
PubMed2001

Polycyclic aromatic hydrocarbon (PAH) emissions from a coal-fired pilot FBC system.

Due to the extensive amount of data suggesting the hazards of these compounds, 16 polycyclic aromatic hydrocarbons (PAHs) are on the Environmental Protection Agency (EPA) Priority Pollutant List. Emissions of these PAHs in the flue gas from the combustion of four coals were measured during four 1000h combustion runs using the 0.1MW heat-input (MWth) bench-scale fluidized bed combustor (FBC). An on-line sampling system was designed for the 16 PAHs, which consisted of a glass wool filter, condenser, glass fiber filter, Teflon filter, and a Tenax trap. The filters and Tenax were extracted by methylene chloride and hexane, respectively, followed by GC/MS analysis using the selective ion monitoring (SIM) mode. In this project, the effects of operating parameters, limestone addition, chlorine content in the coal, and Ca/S molar ratio on the emissions of PAHs were studied. The results indicated that the emissions of PAHs in an FBC system are primarily dependent on the combustion temperature and excess air ratio. The injection of secondary air with high velocity in the freeboard effectively reduces PAH emissions. The addition of extra limestone can promote the formation of PAHs in the FBC system. Chlorine in the coal can possibly lead to large benzene ring PAH formation during combustion. The total PAH emission increases with an increase in the sulfur content of coal. Incomplete combustion results in PAHs with four or more benzene rings. High efficiency combustion results in PAHs with two or three benzene rings.

Air↗
PubMed2001

A combined treatment approach using Fenton's reagent and zero valent iron for the removal of arsenic from drinking water.

Studies on the development of an arsenic remediation approach using Fenton's reagent (H2O2 and Fe(II)) followed by passage through zero valent iron is reported. The efficiency of the process was investigated under various operating conditions. Potable municipal water and ground water samples spiked with arsenic(III) and (V) were used in the investigations. The arsenic content was determined by ICP-QMS. A HPLC-ICPMS procedure was used for the speciation and determination of both As(III) and (V) in the processed samples, to study the effectiveness of the oxidation step and the subsequent removal of the arsenic. The optimisation studies indicate that addition of 100 microl of H2O2 and 100 mg of Fe(II) (as ferrous ammonium sulphate) per litre of water for initial treatment followed by passing through zero valent iron, after a reaction time of 10 min, is capable of removing arsenic to lower than the US Environmental Protection Agency (EPA) guideline value of 10 microg/l, from a starting concentration of 2 mg/l of As(III). Using these suggested amounts, several experiments were carried out at different concentrations of As(III). Residual hydrogen peroxide in the processed samples can be eliminated by subsequent chlorination, making the water, thus, processed, suitable for drinking purposes. This approach is simple and cost effective for use at community levels.

Arsenic↗
PubMed2002

Characterization of inorganic fraction of spent potliners: evaluation of the cyanides and fluorides content.

Spent potliner (SPL) is a solid waste generated by the aluminum industry during the manufacture of aluminum metal in electrolytic cells. Initially the electrolityc cell liners comprise of graphite and carbonaceous materials, but after several years of operation, the liner materials deteriorate and must be removed from the cells. Because of the presence of fluoride and cyanide in the SPL, the US Environmental Protection Agency (USEPA) has listed the materials as a hazardous waste. The purpose of this work was to characterize the extent of leaching of cyanides and fluorides from SPL, as a function of the number of years the material was present in an operating electrolytic cell. At Alumínio Brasileiro S.A. (ALBRAS) plant, SPL was separated into two fractions: a carbon component and an inorganic part. Inorganic materials from nine pots, about 28 tonnes per pot, were examined in this study. When placed in water at a ratio of 20 g solid to 20 ml of water, the pH for all samples varied from 10 to 11.8. The total measured fluoride content of the solid samples varied from 5.13 to 11.41%. However, when leached at a pH of 5, the dissolved fluoride was equivalent to only 0.26-3.46%. With a pH of 12 in the leachate solution, the dissolved fluoride was equivalent to 6.45-9.39%. The data show that the fluorides of the waste are more soluble in basic solutions, and when leached at a pH of 12 are much closer to the actual fluorides content. For the same samples, the dissolved quantity of cyanide was equivalent to 4.34-27.33 ppm, with an average of 13.26 ppm. For all the samples studied, there did not appear to be a correlation between the fractions of fluoride and cyanide leached from the samples and the operating life of the potliner materials.

Aluminum↗
PubMed2003

The leading role and responsibility of the international scientific community in test development.

The possibility that one or more environmental factors may be affecting adversely the endocrine systems of humans and wildlife has been the subject of international study for the past 7 years. Irrespective of which factors are the most important contributors to the perceived problem; the decision has been taken to evaluate synthetic chemicals for such chemical toxicities. This decision requires access to reliable and relevant endocrine disruption (ED) assays. However, few such tests currently exist, albeit many candidate assays are currently under development. Faced with this situation, the US Environmental Protection Agency has taken the lead in supporting the development and validation of appropriate ED assays. Two of these assays, the rodent uterotrophic assay and the Hershberger anti-androgen assay, are in the final stages of validation, a project conducted under the auspices of the Organisation for Economic and Commercial Development. This article describes the particular scientific issues associated with the validation of these two assays and alerts to the continuing need to consider new assay protocols as they become available.

Adenocarcinoma↗
PubMed1999

Absence of neurovisual effects due to tissue and blood cholinesterase depression in a chronic disulfoton feeding study in dogs.

Technical grade disulfoton (DiSyston) was fed to Beagle dogs (four animals per sex and treatment level) at nominal concentrations of 0, 0.5, 4 and 12 ppm for 1 year. The purpose of this study was to characterize the potential general and neurovisual toxicity according to routine Environmental Protection Agency (EPA) guideline requirements, and by use of ancillary ocular and neurologic tests established in this Laboratory. Ophthalmological tests included: ocular tissue cholinesterase and histopathology, electroretinography (ERG), tracking, refractivity, intraocular pressure and pachymetry (corneal thickness) measurements. Neurological examinations included; peripheral and cranial reflex tests, task performance tests, gait and behavioral observations, and rectal temperature measurements. Plasma, erythrocyte and corneal cholinesterase were significantly depressed at 4 and 12 ppm in both sexes. Brain cholinesterase was depressed at 4 and 12 ppm in females. Retinal cholinesterase was depressed at 4 ppm in females and at 12 ppm in males. Ciliary body cholinesterase was depressed at 12 ppm in both sexes. Despite these cholinergic effects, there were no ophthalmologic findings in measurements of ERG, tracking, refractivity, intraocular pressure or pachymetry. There were no clinical neurology findings related to compound administration. We conclude that 0.5 ppm was a no-observable effect level (NOEL), and effects were limited to cholinesterase changes that had no detectable physiologic impact. This study demonstrates that special mechanistic investigations incorporated within guideline studies, enhances scientific integrity and can minimize the need for dedicated organ system studies.

Animals↗
PubMed1999

Monograph: reassessment of human cancer risk of aldrin/dieldrin.

In 1987, the US Environmental Protection Agency (EPA) classified aldrin and dieldrin as category B2 carcinogens, i.e. probable human carcinogens, based largely on the increase in liver tumors in mice fed either organochlorine insecticide. At that date, the relevant epidemiology was deemed inadequate to influence the cancer risk assessment. More time has now elapsed since early exposures of manufacturing workers to aldrin/dieldrin; therefore, updated epidemiological data possess more power to detect exposure-related differences in cancer risk and mortality. Also, recent experimental studies provide a plausible mode of action to explain the mouse specificity of dieldrin-induced hepatocarcinogenesis and call into question the relevance of this activity to human cancer risk. This monograph places this new information within the historic and current perspectives of human cancer risk assessment, including EPA's 1996 Proposed Guidelines for Carcinogen Risk Assessment. Updated epidemiological studies of manufacturing workers in which lifetime exposures to aldrin/dieldrin have been quantified do not indicate increased mortality or cancer risk. In fact, at the middle range of exposures, there is evidence of a decrease in both mortality from all causes and cancer. Recent experimental studies indicate that dieldrin-induced hepatocarcinogenesis in mice occurs through a nongenotoxic mode of action, in which the slow oxidative metabolism of dieldrin is accompanied by an increased production of reactive oxygen species, depletion of hepatic antioxidant defenses (particularly alpha-tocopherol), and peroxidation of liver lipids. Dieldrin-induced oxidative stress or its sequelae apparently result in modulation of gene expression that favors expansion of initiated mouse, but not rat, liver cells; thus, dieldrin acts as a nongenotoxic promoter/accelerator of background liver tumorigenesis in the mouse. Within the framework of EPA's Proposed Guidelines for Carcinogen Risk Assessment, it is proposed that the most appropriate cancer risk descriptor for aldrin/dieldrin, relating to the mouse liver tumor response, is 'not likely a human carcinogen', a descriptor consistent with the example of phenobarbital cited by EPA.

Aldrin↗
PubMedDate not supplied

Effects of the neurotoxin 3,3'-iminodipropionitrile on acoustic startle and locomotor activity in rats: a comparison of functional observational and automated startle assessment methods.

Iminodipropionitrile (IDPN) is a neurotoxin that has been used in the validation of the U.S. Environmental Protection Agency's Functional Observational Battery (FOB), including acoustic startle. We compared the FOB clicker startle method to an automated procedure. IDPN was administered IP to male Long-Evans rats in three daily doses of 0, 100, 200, or 400 mg/kg (N = 8 per group). There was a significant effect of IDPN on clicker startle that was attributable to reduced startle in the IDPN-400 group. There were multiple significant effects of IDPN on automated startle. The overall effect of IDPN on automated startle was to reduce startle amplitude in the IDPN-400 and -200 groups. In addition, the IDPN-400 group showed startle reductions on all days, whereas the IDPN-200 group showed reduced startle primarily on day 1. IDPN also significantly altered locomotor activity, which was included as an internal check on IDPN's efficacy. The typical pattern of hypolocomotion was found on day 2 posttreatment in the IDPN-400 and -200 groups, followed by hyperlocomotion on all subsequent days in the IDPN-400 group. The startle results demonstrated that automated startle is more sensitive (at least for IDPN treatment), eliminates observer judgments, and provides interval-scaled data compared to the clicker method. However, automated startle also requires additional initial cost and more testing time per animal when multiple trials are presented.

Animals↗
PubMed2001

Chemical durability of glasses obtained by vitrification of industrial wastes.

The vitrification of zinc-hydrometallurgy wastes, electric arc furnace dust (EAFD), drainage mud, and granite mud was shown to immobilize the hazardous components in these wastes. Batch compositions were prepared by mixing the wastes with glass-cullet and sand to force the final glass composition into the glass forming region of the SiO2-Fe2O3-(CaO, MgO) system. The vitrification was carried out in the 1400-1450 degrees C temperature range followed by quenching in water or on stainless steel mold. The United States (US) Environmental Protection Agency (EPA) toxic characterization leaching procedure (TCLP) test was used as a standard method for evaluating the leachability of the elements in the glasses and glass-ceramics samples made with different percentages of wastes. The results for EAFD glasses highlighted that the chemical stability is influenced by the glass structure formed, which, in turn, depends on the Si/O ratio in the glass. The chemical durability of jarosite glasses and glass-ceramics was evaluated by 24 h contact in NaOH, HCl and Na2CO3, at 95 degrees C. Jarosite glass-ceramics containing pyroxene (J40) are more durable than the parent glass in HCl. Jarosite glass-ceramics containing magnetite type spinels (J50) have a durability similar to the parent glass and even lower in HCl because the magnetite is soluble in HCl.

Ceramics↗
PubMed2003

Recycling of spent nickel-cadmium batteries based on bioleaching process.

Only 1-2 percent of discarded dry batteries are recovered in China. It is necessary to find an economic and environmentally friendly process to recycle dry batteries in this developing country. Bioleaching is one of the few techniques applicable for the recovery of the toxic metals from hazardous spent batteries. Its principle is the microbial production of sulphuric acid and simultaneous leaching of metals. In this study, a system consisting of a bioreactor, settling tank and leaching reactor was developed to leach metals from nickel-cadmium batteries. Indigenous thiobacilli, proliferated by using nutritive elements in sewage sludge and elemental sulphur as substrates, was employed in the bioreactor to produce sulphuric acid. The overflow from the bioreactor was conducted into the settling tank. The supernatant in the settling tank was conducted into the leaching reactor, which contained the anode and cathodic electrodes obtained from nickel-cadmium batteries. The results showed that this system was valid to leach metals from nickel-cadmium batteries, and that the sludge drained from the bottom of the settling tank could satisfy the requirements of environmental protection agencies regarding agricultural use.

Agriculture↗
PubMed2003

Bioeffects of microwave--a brief review.

Since the 18th century scientists have been intrigued by the interaction of electromagnetic fields (EMFs) and various life processes. Attention has been focussed on EMFs in different frequency ranges, of which microwave frequency range forms an important part. Microwaves are part of the electromagnetic spectrum and are considered to be that radiation ranging in frequency from 300 million cycles per second (300 MHz) to 300 billion cycles per second (300 GHz), which correspond to a wavelength range of 1 m down to 1 mm. This nonionising electromagnetic radiation is absorbed at molecular level and manifests as changes in vibrational energy of the molecules or heat (Microwaves irradiating the community, Hidden hazards, Bantan Books publisher, Australia, 1991). Identifying and evaluating the biological effects of microwaves have been complex and controversial. Because of the paucity of information on the mechanism of interaction between microwave and biological systems, there has been a persistent view in physical and engineering sciences, that microwave fields are incapable of inducing bioeffects other than by heating (Health Physics 61 (1991) 3). Of late, the nonthermal effects of microwaves on tissue responses are being documented (Physiol. Rev. 61 (1981) 435; Annals of New York Acad. Sci. 247 (1975) 232; J. Microwave Power 14 (1979) 351; Bioelectromagnetics 7 (1986a) 45; Bioelectromagnetics 7 (1986b) 315; Biologic Effects and Health Hazards of Microwave Radiation, Warsaw, Polish Medical Publication (1974) 289; Biologic Effects and Health hazards of the microwave Radiation, Warsaw, Polish Medical Publication (1974) 22; Multidisciplinory perspectives in event-related brain potential research, Washington DC, US Environmental Protection Agency, (1978) 444). The present article is an attempt to familiarise the reader with pertinent information regarding the effects, mainly athermal, of microwave irradiation on biologic systems, especially microorganisms.

Animals↗
PubMed2004

A dispersion modelling approach to determining the odour impact of intensive pig production units in Ireland.

It is becoming more common now to use atmospheric dispersion models to predict where odour nuisance is likely to occur near pig units. An odour threshold concentration of 1 OuE m(-3) is the level at which an odour is detectable by 50% of screened panellists. A new odour annoyance criterion (C(98,1-h) (98%-ile, 1-h average odour concentration) < or = 4.3 OuE m(-3)) was developed in this study and compared to the Environmental Protection Agency (EPA) (Ireland) recommendation (C(98,1-h)< or = 6 OuE m(-3)) using the ISCST3 model with data from three meteorological stations. Abatement techniques such as exhaust vent modification, feed manipulation, and biofiltration were assessed. Based on current limits (C(98,1-h)< or = 6 OuE m(-3)) for existing facilities, predicted setback distances can be up to 780 m for a 1000-sow unit, depending on which meteorological data set is used. However, if using the suggested odour impact criterion in this research (C(98,1-h)< or = 4.3 OuE m(-3)), setback distances could reach a maximum of 1000 m. Biofilters on second stage weaning and finishing pig buildings offer the greatest single reduction (up to 650 m) in odour impact. When combined with feed manipulation and increased exhaust air velocity, the figure can be as high as 920 m. Due to the critical requirement for local meteorological data, it is recommended that a meteorological station be installed on large pig units to facilitate more accurate predictions. Site measurements of odour emissions should be made in each case because emissions are influenced by a range of local factors including feed, manure management, building design and operation.

Agriculture↗
PubMed2006

Effect of sodium sulfite on mast cell degranulation and oxidant stress.

BACKGROUND: Sulfur dioxide is 1 of 6 environmental pollutants monitored by the Environmental Protection Agency. Its ability to induce bronchoconstriction is well documented. It is highly soluble, initially forming sulfite ions in solution. Sulfur oxides are important constituents of other pollutants, such as diesel exhaust and fine particulates. OBJECTIVE: To investigate the cellular responses of sulfite on cultured mast cells (rat basophilic leukemia [RBL-2H3] cells) and human peripheral blood basophils. METHODS: Sulfite-induced mast cell degranulation and intracellular production of reactive oxygen species were evaluated in the presence and absence of antioxidants and inhibitors of redox metabolism. Degranulation was determined using beta-hexosaminidase, serotonin, and histamine release assays. Induction of intracellular reactive oxygen species generation was determined using the redox-sensitive dye 2',7'-dichlorofluorescein diacetate. RESULTS: Sodium sulfite induced degranulation and the generation of intracellular reactive oxygen species in RBL-2H3 cells. These responses were inhibited by the free radical scavenger tetramethylthiourea and the flavoenzyme inhibitor diphenyliodinium but not by depletion of extracellular calcium. Peripheral blood basophils also showed histamine release after exposure to sodium sulfite CONCLUSIONS: Sulfite, the aqueous ion of sulfur dioxide, induces cellular activation, leading to degranulation in mast cells through a non-IgE-dependent pathway. The response also differs from IgE-mediated degranulation in that it is insensitive to the influx of extracellular calcium. The putative pathway seems to rely on activation of the reduced form of nicotinamide adenine dinucleotide phosphate oxidase complex, leading to intracellular oxidative stress.

Animals↗
PubMed2002

Particulate matter, PM 10 & PM 2.5 levels, and airborne mutagenicity in Chiang Mai, Thailand.

Daily levels of particulate matter (PM) in the ambient air (PM 2.5 and PM 10) were measured in a northern city of Thailand (Chiang Mai) from March 1998 to October 1999. Twenty-four-hour air particulate matter samples were collected each day with Airmetric Minivol portable air samplers. Monthly averages of PM 2.5 from four stations in Chiang Mai varied from 15.39 to 138.31microg/m(3) and 27.29 to 173.40 microg/m(3) for PM 10. The PM 2.5 annual average was 58.48 mg/m(3) and PM 10, 86.38 microg/m(3). Daily PM 2.5 (24h values) during the winter months in Chiang Mai frequently exceeded 200-300 microg/m(3). The maximum concentrations of PM 2.5 (24h average) in Chiang Mai air from December 1998 to April 1999 were 2.8-, 3.5-, 4.2-, 6.5- and 3.2-fold higher than the US Environmental Protection Agency (US EPA), PM 2.5, 24h standard of 65 microg/m(3). From May to October, the mean 24h levels of PM 2.5 and PM 10 were at acceptable levels. The data shows that during the winter season (December to March), levels of PM 2.5 and PM 10 in the Chiang Mai atmosphere are very high, and there may be significant health implications associated with these high concentrations. During the summer season, the fine particles were generally within the acceptable levels. To our knowledge, these are the first measurements of PM 2.5 to be reported for the city of Chiang Mai and they indicate considerable ambient fine particle exposures to the Chiang Mai population. In addition, dichloromethane extracts of airborne particulate matter PM 2.5 or PM 10 collected in the months of winter in the city of Chiang Mai were mutagenic to Salmonella typhimurium strain TA100 without metabolic activation. The mutagenicity appeared to track particle concentrations and increased in the presence of S9 mix.

Air Pollutants↗
PubMed2000

Modeling the mouse lymphoma forward mutational assay: the Gene-Tox program database.

An SAR model of the induction of mutations at the tk(+/-) locus of L5178Y mouse lymphoma cells (MLA, for mouse lymphoma assay) was derived based upon a re-evaluation of experimental results reported by a Gene-Tox (GT) working group [A.D. Mitchell, A.E. Auletta, D. Clive, P.E. Kirby, M.M. Moore, B.C. Myhr, The L5178Y/tk(+/-) mouse lymphoma specific gene and chromosomal mutation assay. A phase III report of the U.S. Environmental Protection Agency Gene-Tox Program, Mutation Res. 394 (1997) 177-303.]. The predictive performance of the GT MLA SAR model was similar to that of a Salmonella mutagenicity model containing the same number of chemicals. However, the structural determinants (biophores) derived from the GT MLA SAR model include both electrophilic as well as non-electrophilic moieties, suggesting that the induction of mutations in the MLA may occur by both direct interaction with DNA and by non-DNA-related mechanisms. This was confirmed by the observation that the set of biophores associated with MLA overlapped significantly with those associated with phenomena related to loss of heterozygosity, chromosomal rearrangements and aneuploidy. The MLA SAR model derived from the GT data evaluation was significantly more predictive than an SAR model previously derived from MLA data reported by the US National Toxicology Program [B. Henry, S.G. Grant, G. Klopman, H.S. Rosenkranz, Induction of forward mutations at the thymidine kinase locus of mouse lymphoma cells: evidence for electrophilic and non-electrophilic mechanisms, Mutation Res. 397 (1998) 331-335.]. Moreover, the latter model appeared to be more complex than the former, suggesting that the GT induction data was both simpler mechanistically and more homogeneous than that of the NTP.

Animals↗
PubMed2002

A survey of EPA/OPP and open literature on selected pesticide chemicals. III. Mutagenicity and carcinogenicity of benomyl and carbendazim.

The known aneuploidogens, benomyl and its metabolite, carbendazim (methyl 2-benzimidazole carbamate (MBC)), were selected for the third in a series of ongoing projects with selected pesticides. Mutagenicity and carcinogenicity data submitted to the US Environmental Protection Agency's (US EPA's) Office of Pesticide Programs (OPP) as part of the registration process are examined along with data from the open literature. Mutagenicity and carcinogenicity profiles are developed to provide a complete overview and to determine whether an association can be made between benomyl- and MBC-induced mouse liver tumors and aneuploidy. Since aneuploidogens are considered to indirectly affect DNA, the framework adopted by the Agency for evaluating any mode of action (MOA) for carcinogenesis is applied to the benomyl/MBC data. Both agents displayed consistent, positive results for aneuploidy induction but mostly negative results for gene mutations. Non-linear dose responses were seen both in vitro and in vivo for aneuploidy endpoints. No evidence was found suggesting that an alternative MOA other than aneuploidy may be operative. The data show that by 14 days of benomyl treatment, events associated with liver toxicity appear to set in motion the sequence of actions that leads to neoplasms. Genetic changes (as indicated by spindle impairment leading to missegregation of chromosomes, micronucleus induction and subsequent aneuploidy in bone marrow cells) can commence within 1-24h after dosing, well within the time frame for early key events. Critical steps associated with frank tumor formation in the mouse liver include hepatotoxicity, increased liver weights, cell proliferation, hypertrophy, and other steps involving hepatocellular alteration and eventual progression to neoplasms. The analysis, however, reveals weaknesses in the data base for both agents (i.e. no studies on mouse tubulin binding, no in vivo assays of aneuploidy on the target tissue (liver), and no clear data on cell proliferation relative to dose response and time dependency). The deficiencies in defining the MOA for benomyl/MBC introduce uncertainties into the analysis; consequently, benomyl/MBC induction of aneuploidy cannot be definitively linked to mouse liver carcinogenicity at this time.

Animals↗