Views on chemical safety information and influences on chemical disposal behaviour in the UK.

This study examined how groups representing four tiers in the chemical supply chain (manufacturers, vendors, workers and consumers) understood safety information, and the factors that influenced disposal behaviour. Data from seven, semi-structured, focus groups was analysed both qualitatively (textual analysis) and quantitatively (network analysis). Such combined analytical methods enabled us to achieve both detailed insights into perceptions and behaviour and an objective understanding of the prevailing opinions that occurred within and between the focus group discussions. We found issues around awareness, trust, access and disposal behaviours differed between groups within the supply chain. Participants from the lower tiers perceived chemical safety information to be largely inaccessible. Labels were the main source of information on chemical risks for the middle and bottom tiers of the supply chain. Almost all of the participants were aware of the St Andrew's Cross and skull and crossbones symbols but few were familiar with the Volatile Organic Compound logo or the fish and tree symbol. Both the network and thematic analysis demonstrated that whilst frequent references to health risks associated with chemicals were made environmental risks were usually only articulated after prompting. It is clear that the issues surrounding public understanding of chemical safety labels are highly complex and this is compounded by inconsistencies in the cognitive profiles of chemical users. Substantially different cognitive profiles are likely to contribute towards communication difficulties between different tiers of the supply chain. Further research is needed to examine the most effective ways of communicating chemical hazards information to the public. The findings demonstrate a need to improve and simplify disposal guidance to members of the public, to raise public awareness of the graphic symbols in the CHIP 3.1, 2005 regulations and to improve access to disposal guidance.

Absorption, metabolism and excretion of 4-chloro-2-methylphenoxyacetic acid (MCPA) in rat and dog.

1. The oral no overall adverse effect level (NOAEL) for chronic toxicity of 4-chloro-2-methylphenoxyacetic acid (MCPA) in rat is approximately 1.3 mg kg(-1) and in dog is 0.2 mg kg(-1). In an attempt to explain the difference in toxicology between these species, rats and dogs were orally dosed with (14C)-MCPA at 5 or 100 mgkg(-1) and plasma toxicokinetics, rates and routes of excretion and biotransformation were investigated. 2. Elimination of radioactivity in rat plasma was biphasic and in dog was monophasic. Rat eliminated radioactivity from plasma significantly faster than dog (approximate values biased on total radioactivity: 5 mg kg(-1) rat: t 1/2 dist 3.5 h, t 1/2 elim 17.2-36.2 h, AUC(0-infinity) 230 microg equiv hg(-1); 5 mg kg(-1) dog: t 1/2 47h, AUC(0-infinity) 2,500 microg equiv h g(-1); 100 mg kg(-1) rat: t 1/2 dist 10h, t 1/2 elim 10.27-25.4h, AUC(0-infinity) 5,400 microg equiv hg(-1); l00 mg kg(-1) dog: t 1/2 h, AUC(0-infinity) 20,500 microg eqiv h g(-1). 3. For both species, the principal route of excretion was in urine but renal elimination was notably more rapid and more extensive in rat. 4. In both rat and dog, excretion of radioactivity was mainly as MCPA and its hydroxylated metabolite hydroxymethylphenoxyacetic acid (HMCPA). In rat, both were mainly excreted as the free acids although a small proportion was conjugated. In dog, the proportion of HMCPA was increased and the majority of both species was excreted as glycine or taurine conjugates. 5. These data, along with previously published accounts, indicate that renal elimination of MCPA in dog is substantially slower than in rat resulting in disproportionate elevation of AUC (based on total radioactivity) in dog compared with rat.

Reproductive toxicity of MCPA (4-chloro-2-methylphenoxyacetic acid) in the rat.

The reproductive effects of the administration of 4-chloro-2-methylphenoxyacetic acid (MCPA) to rats were evaluated through two generations, from prior to mating, throughout mating, to gestation and lactation. MCPA was administered in the diet at doses of 0, 50, 150, or 450 ppm to 25 male and female immature rats (F0 parents) for 10 weeks. F0 parents were then mated to produce a first litter (F1a), retained only until weaning, and were subsequently remated to produce a second litter, F1b. Groups of male and female F1b animals were then dosed as were their parents for 10 weeks postweaning, and the breeding was repeated to produce F2a and F2b animals. The study concluded with the F2b weanlings. MCPA was administered continuously throughout the study. Only minimal, non-treatment-related observations were noted, which included rhinorrhea (in both treated and control animals in the F0 generation) and malocclusion and alopecia (in both the F0 and F1b generations). There were no consistent dose-related effects on reproductive function for parental animals of either sex in either generation. Statistically significant differences were noted in body weights and body weight gains in the 450-ppm dose group for both male and female pups in F2a and F2b. There were no treatment-related macroscopic or microscopic observations noted for any animal in this study. The no-observable-effect level (NOEL) for reproductive function in rats administered MCPA continuously for two successive generations was determined to be 450 ppm (approximately 22 mg/kg/day). The NOEL for general systemic toxicity, based on body weight effects in adult animals in the F1b generation was 150 ppm. The NOEL for effects on the offspring of the F1b generation, manifested as reduced pup weights and pup weight gains was also 150 ppm (approximately 8 mg/kg/day). Based upon the results of this study, MCPA, administered for two generations to Crl:CD(SD)BR Albino rats, is considered not to be a reproductive toxicant.

Hyperplastic and Neoplastic Changes in the Lungs of Rats Treated Concurrently with Chrysotile Asbestos and N-Nitrosoheptamethyleneimine.

This study investigated the combined effect in rat lungs of simultaneous exposure to chrysotile asbestos and N-nitrosoheptamethyleneimine (NHMI), with the objective of determining the potential for chrysotile to promote or otherwise enhance the pathological responses to this potent rodent lung carcinogen. Groups of 15 or 20 male and female animals were treated with 0, 3, or 10 mg kg(-1) NHMI subcutaneously, once a week for 10 wk, plus either clean air (control) or 50 mg m(-3) chrysotile by nose-only inhalation for 4 wk. A broad range of pulmonary metaplastic, hyperplastic, and neoplastic lesions was observed. Effects were more marked in male than in female animals. NHMI treatment increased the incidence of hyperplastic lesions, with apparent augmentation by chrysotile exposure (not statistically significant). Similarly, a "promoting" effect of chrysotile in the induction of lung tumors was observed, with all but 2 of the 11 primary tumors detected being in animals treated with both NHMI and asbestos. However, this apparent interaction was again not confirmable statistically, probably because of the low number of observed tumors (stemming from premature termination of the experiment). The study results are in line with those of similar previous studies, which found a higher incidence of hyperplastic and neoplastic changes in animals treated with both nitrosamine and asbestos than in those given nitrosamine alone. It is proposed that the method described (with minor modification) could be used to investigate either (1) the ability of other inhaled particles to augment NHMI carcinogenicity, or (2) the propensity of other chemical carcinogens to interact with asbestos in the production of pulmonary neoplasms.

Comparative hazards of chrysotile asbestos and its substitutes: A European perspective.

Although the use of amphibole asbestos (crocidolite and amosite) has been banned in most European countries because of its known effects on the lung and pleura, chrysotile asbestos remains in use in a number of widely used products, notably asbestos cement and friction linings in vehicle brakes and clutches. A ban on chrysotile throughout the European Union for these remaining applications is currently under consideration, but this requires confidence in the safety of substitute materials. The main substitutes for the residual uses of chrysotile are p-aramid, polyvinyl alcohol (PVA), and cellulose fibers, and it is these materials that are evaluated here. Because it critically affects both exposure concentrations and deposition in the lung, diameter is a key determinant of the intrinsic hazard of a fiber; the propensity of a material to release fibers into the air is also important. It is generally accepted that to be pathogenic to the lung or pleura, fibers must be long, thin, and durable; fiber chemistry may also be significant. These basic principles are used in a pragmatic way to form a judgement on the relative safety of the substitute materials, taking into account what is known about their hazardous properties and also the potential for uncontrolled exposures during a lifetime of use (including disposal). We conclude that chrysotile asbestos is intrinsically more hazardous than p-aramid, PVA, or cellulose fibers and that its continued use in asbestos-cement products and friction materials is not justifiable in the face of available technically adequate substitutes.

Chronic dietary toxicity and oncogenicity evaluation of MCPA (4-chloro-2-methylphenoxyacetic acid) in rodents.

The chronic toxicity and oncogenicity of 4-chloro-2-methylphenoxyacetic acid (MCPA) were evaluated in Wistar rats at target doses of 20, 80, and 320 ppm for 2 years. Chronic effects were noted in male and/or female rats in the 80- and 320-ppm dose groups, namely elevations in triglycerides and serum glutamic transaminase levels. Nephrotoxicity was confined to male rats in the 320-ppm dose group. The systemic NOEL was determined to be 20 ppm for male and female rats. No oncogenic potential was observed. Doses in the 2-year oncogenicity study in mice were 20, 100, and 500 ppm. Kidney weight changes with corresponding minor histopathological findings in the kidney were evident in females in the 500-ppm dose group. MCPA was determined to have no oncogenic potential in B6C3F1 mice. In summary, there is no evidence of any oncogenic potential after dietary exposure of MCPA in rats or mice even at doses where limited chronic toxicity is seen.

Heat-Pasteurization Process for Inactivation of Nonproteolytic Types of Clostridium botulinum in Picked Dungeness Crabmeat.

Development of a heat-pasteurization process is described for picked meat of Dungeness crabs ( Cancer magister ) contained in oxygen-impermeable flexible pouches, For each time-temperature treatment, 30 samples, each inoculated with an equal mixture of three strains of C. botulinum nonproteolytic type B, for a total of 107 spores, provided the basis for calculation of the thermal resistance (a 7D process). Following heat processing, the crabmeat was removed from the pouches and transferred to enrichment medium where it was incubated anaerobically for 150 days. Endpoints at which spores survived were determined by the presence of toxin in the enrichment medium. Process times ranged from 90 min at 88.9°C to 20.3 min at 94.4°C. D values (the time at each temperature required to reduce the inoculum by 1 log) ranged from 12.9 for the 88.9°C process to 2.9 for the 94.4°C process. The relative sterilization value, F0 was .054 and the pasteurization value, , was 240. This pasteurization process safely extends refrigerated shelf life by inactivating spores of Clostridium botulinum nonproteolytic types B, E, and F and also non-spore-forming pathogens such as Listeria monocytogenes . The process does not, however, inactivate the heat-resistant proteolytic strains of C. botulinum or other more heat-resistant spore-formers. The packages and master cartons of the pasteurized product, therefore, should be labeled "Keep refrigerated-Continuous refrigeration below 38°F (3.3°C) required."

The effects of intrapleural injections of alumina and aluminosilicate (ceramic) fibres.

Groups of rats, 24 male and 24 female, approximately 8 weeks old, were dosed by a single intrapleural injection with a saline suspension of refractory alumina fibres (Saffil fibres ICI plc) either as manufactured or after extensive thermal ageing; or one of two aluminosilicate ('ceramic') fibres with different diameter distributions. Similar groups were dosed with a suspension of UICC chrysotile A asbestos or saline solution to serve as positive and negative controls respectively. Rats were maintained to 85% mortality and all decedents and terminal sacrifices were closely examined for the presence of mesothelioma. Malignant mesothelioma was diagnosed in ten rats, seven dosed with asbestos and three dosed with aluminosilicate fibre B. No mesothelioma was detected in any rat dosed with Saffil fibres or aluminosilicate fibre A or in negative controls. The results support the predicted inert nature of Saffil alumina fibres and provide further evidence for the importance of fibre dimension in the induction of mesothelioma. The implication of the results for inhalation exposures is discussed.

The effects of diet on the incidence of periodontitis in rats.

Four groups of 60 male Alpk:APfSD rats were fed different nutritionally comparable diets for 107 weeks with interim sacrifices at 26, 53 and 77 weeks in order to compare the effect of diet on the incidence of oral disease. Changes in the oral and nasal cavities were assessed by histopathology. Oro-nasal fistulation and severe periodontitis were associated with diets containing fibres originating from oats and barley. An expanded ground diet induced the most severe lesions. Aspects of the pathogenesis of the lesions observed are discussed.

Olfactory and hepatic changes following a single inhalation exposure of 3-trifluoromethyl pyridine in rats: concentration and temporal aspects.

The effects of a single exposure to 3-trifluoromethyl pyridine (3FMP), were investigated in two studies. In the first study, rats were exposed nose only to 0, 50 or 800 ppm 3FMP for periods of 15 min to 4 h. Half were sacrificed on day 3 and the remainder on day 10. In the second study, rats were exposed whole body to 0, 0.1, 1.0, 10 or 50 ppm 3FMP for 6 h, with sacrifices immediately after exposure (6 h), 24 h and on days 3 (48 h after exposure started) 5, 8, 11, 35, 70 and 157. Effects were seen in the olfactory epithelium at concentrations of 1 ppm and above and in the liver at concentrations of 50 ppm and above. In the olfactory epithelium the earliest changes were seen immediately after exposure and by 24 h this progressed to extensive necrosis with sloughing of the epithelium. By day 3, the epithelium was replaced by undifferentiated basophilic cells, considered to reflect early regeneration. Regeneration progressed to complete recovery between days 70 and 157, no changes were seen in the nasal respiratory epithelium, an olfactory function test on rats exposed for 6 h to 50 or 10 ppm 3FMP showed a reduced sense of olfaction at days 3 and 5 with complete recovery on subsequent days, indicating functional recovery in advance of histological normality. Single cell necrosis was seen in the liver at day 3 after 30 min exposure and immediately after 6 h exposure to 50 ppm 3FMP. At 24 h after a 6 h exposure to 50 ppm this had progressed to necrosis, haemorrhage and moderate cytoplasmic hepatocyte vacuolation in centrilobular areas. The lesion had completely recovered by day 5.

A protocol to evaluate the fibrogenic potential of inhaled materials.

A protocol to provide a more rapid assessment of the fibrogenic potential of an inhaled particulate has been developed. Young rats are exposed nose-only for 6 h/day, 7 days a week for 28 days to a respirable aerosol of the test compound. After exposure the rats are kept for up to 1 year, followed by histopathological assessment of the lung. Interim sacrifices could allow an estimate of the rate and severity of the development of any fibrogenic lesion. The protocol has been evaluated for chrysotile asbestos, alpha-quartz and titanium dioxide using rats of both sexes and two different ages at first exposure. The results indicate that there are no significant differences in either the rate, type or extent of lesion provoked by a 28-day exposure period when compared with the more conventional 1-year exposure period studies. It can be concluded that neither sex nor age at first exposure cause any biologically significant differences in response, although young rats would be used in practice. Only one sex need be investigated. The protocol offers considerable benefits over conventional inhalation studies for fibrogenicity (where a 1-year exposure period followed by a further 1-year holding period is usual) by virtue of time, specificity (in the absence of continued exposure the development of any lesion can be studied free from initial inflammatory response) and cost, and could be incorporated into a standard subacute inhalation study design. The results obtained are also of more physiological relevance than studies based on intratracheal instillation.

Olfactory and hepatic changes following inhalation of 3-trifluoromethyl pyridine in rats.

Rats exposed by inhalation to 3-trifluoromethylpyridine (3-FMP) for 10, 30 or 90 days showed an unusual response in the nasal passages. Focal histological change including reduction in the number of cell layers, disorganisation, vacuolation and minimal necrosis was confined to the olfactory epithelium. Axon bundles and the olfactory bulb were unaffected but there was loss of PAS staining affinity in Bowman's glands. The onset of the lesion showed a very steep dose-relationship approximating a quantal response; no effects were seen after 90 days exposure to 0.1 ppm but the changes were fully developed after 30 days exposure to 0.5 ppm. There was no marked progression with either increased exposure concentrations (up to 329 ppm) or with increased duration of exposure (10-90 days). The respiratory epithelium was generally unaffected apart from a mild irritant response seen only after 90 days. Exposures also resulted in a response in the liver. Centrilobular and midzonal vacuolation was observed at 10 and 30 days following exposures at or above 5 ppm 3-FMP and the severity increased with concentration. The lesion regressed with time even when exposure continued and only minimal changes were evident after 90 days, probably indicating an adaptive response. This work demonstrates the high organ specificity of 3-FMP, particularly for the olfactory epithelium.

Effects of nonfibrous minerals in the V79-4 cytotoxicity test.

The use of the V79-4 system as a primary screen for fiber carcinogenicity is dependent on the observed correlation between cytotoxicity of the test material in the system and mesothelioma following intrapleural injection in animals. This correlation has been established for relatively pure samples of fibrous minerals. The wider application of the system as a screen for industrial dusts may depend on the ability of the system to show an unequivocal response to small yet significant percentages of fibrous dust in the presence of a large excess of nonfibrous material. Some materials tested, including platy minerals, show a response in the test which, while clearly less than that from UICC asbestos samples, could be construed as a positive result. Some, though not all, of these minerals show a nonlinear dose response in the test. This anomalous dose response may aid in the identification of some false positive results but the variety of responses to nonfibrous minerals places a limit on the predictive value of the test mixtures. Results obtained from mixtures of "standard" dust samples suggest this limit is reached at or above 10% fibrous content. Such levels would be significant in terms of human exposure. Extension of the concentration range tested does not improve the predictive value of the test.

In vitro RPM fibrogenic potential assay of welding fumes.

The fibrogenic potential of 11 different welding fumes and metallic aerosols, considered to be reference standard surrogates for the commonly used welding technologies and applications responsible for 70% of welders exposure, is screened by using the rat peritoneal macrophage (RPM) in vitro bioassay. Only one class of fumes, that from the manual metal are welding of stainless steel, shows distinct fibrogenic potential. This fume, however, is not common to more than four or five of the heretofore 90 cases of pulmonary fibrosis reported among welders. Thus, although insoluble Cr(VI) is probably the active fibrogen in stainless steel fumes, an etiological factor common to all fibrogenic welding exposures must be sought; it is tentatively proposed to be NO chi, a potent experimental in vivo fibrogen copiously produced by certain welding processes and ubiquitous at low concentrations in the welding environment.

Fibrogenic potential of welding fumes.

A search of 3600 indexed pathology cases has disclosed pulmonary fibrosis in 29 welders. Scanning electron microscopy of biopsy material revealed macrophages laden with inorganic particulates which have characteristics compatible with welding aerosols. In order to establish a possible relationship between fibrotic reaction and welding-fume exposure, the fibrogenic potential fo some 11 different welding fumes and metallic aerosols, considered to be reference standard surrogates for the commonly used welding technologies and applications responsible for 70% of welders exposure, were screened using the Rat Peritoneal Macrophage in vitro bioassay. Only one class of fumes, that from the manual metal arc welding of stainless steel, showed distinct fibrogenic potential. This fume is, however, not common to more than four or five of the heretofore 90 cases of pulmonary fibrosis reported among welders. Thus, although insoluble Cr(VI) is probably the active fibrogen in stainless steel fumes, an etiological factor common to all fibrogenic welding exposures must be sought. It is tentatively proposed to be NO2, a potential experimental in vivo fibrogen copiously produced by certain welding processes and ubiquitous at low concentrations in the welding environment.