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Methyl chloride and behaviour
140
Food additivesandcontaminants-FdChem.Toxic.Vol. 20,No. I
died or were killed (when moribund) and various Of the 179exposedsubjects31%(55)gave a history organs, including the entire gastro-intestinaltract of asthmaand/or,hay fever and 397”(70)were classed as atopic. Among the small group of non-exposed wereexaminedfor tumours. Tumours developedin go”/:, of the germ-freerats subjects357; wereclassedasatopic. Forty-nine, (27%) and 94”/”of the conventional rats with averagelatent of the exposedsubjectshad symptomsrelating to aniperiods of 11.7 and 13.7 months respectively. The mal contact, most commonly rhinitis but sometimes averagenumbersof tumours were 4*6/germ-freerat alsoasthma,and rashesand local urticaria often foland 4.4/conventionalrat. Apart from three germ-free lowedanimalscratchesor contact with urine or paws. rats with caecaltumoursall of the intestinal tumours The symptomsin most caseswere relatively minor were located in the distal part of the ileum. Of the but they occasionallypreventedfurther contact with germ-freerats six had ileal adenomas,three had cae- animals.There was no overall tendency for the more cal adenomas.one had an adrenocortical adenoma heavily exposedhandlersto have more allergicsympand nine had sarcomas. Of the conventionalrats eight toms than the usersalthough handlersdid develop hab ileal adenomas,ten had iliac adenocarcinomas, symptomsmore quickly than users.There wasno asone had a papillomaof the urinary bladder, two had sociationbetweenskin-test atopic status and sympadrenocorticaladenomasand five had iliac sarcomas. toms from animal contact with the exception of The sarcomasof germ-free rats were larger. more asthma.Subjectswith a previous history of asthma numerousand more rapidly growing than those of were more likely to develop animal-relatedasthma conventional rats. The non-intestinal tumours were but no morelikely to developother symptoms.Smokone adrenocorticaladenomain a germ-freerat and ing history wasnot relatedto symptomsfrom animal two adrenocortical adenomas and one bladder contact. Of the 179exposedsubjects29 had a positive reaction.to at leastone of the animal extracts after tumour in conventionalrats. There was no apparent difference betweengerm- 15min and this skin reactivity was positively associfree and conventional rats in tumour incidence ated with a history of symptomsfrom animal contact althoughthe absenceof gut microflora wasassociated although most of this associationwas due to the with a shorter latent period, increasedsusceptibility strongassociationbetweenskin reactivity and asthma to sarcomasand reduced susceptibility to adeno- from animal contact. Skin reactivity to animal carcinomas.The authorssuggestthat thesedifferences extracts was also associatedwith skin-test atopic were relatedto somedegradationof the bracken car- status. No precipitins were detected in the sera of cinogenby the gut microflora in conventionalrats. subjectsby gel diffusion against the animal extracts. [In view of the smallnumbersof animalsinvolved The enzyme-linkedimmunosorbentassayshowedno and the absenceof a control group theseresultscan significant differences in IgG levels between the variousgroups. only be regardedasa preliminary indication.] The authorsconsideredthat their resultsmay have Laboratory animals-turning the tables? underestimatedthe total number of allergy sufferers especially since many of the workers had only Cockcroft. A., Edwards.J.. McCarthy. P. & Anders- recently joined the units and may not have experison.N. (1981).Allergy in laboratory animal workers. enced symptoms,whilst the worst casesmay have given up working with animals completely. This Ltrncer I, 827. secondfactor may have had quite a significanteffect Nearly 32,000peoplework with laboratory animals sinceLutsky & Neuman(Ann. Allergy 1975.35, 201) in the UK and symptomsof allergy. particularly rhi- found that 28:; of the workers who were allergic to in the USA subsenitis and asthma,seemto be quite common. Many animaldanderin 39 establishments more peopleare exposedto animalsin different situ- quently changedjobs or avoidedcontact with specific ations and there have beena number of reports of animalspecies. Only five individualsshowedskin reactivity in the allergic reactions(includingone to elephants!). Cockcroft er al. have investigatedthe extent and absenceof symptomssuggestingthat skin tests are nature of the animal allergy problem in three MRC unlikely to be usefulasa prescreenfor peoplelikely establishments. A questionnairedetailing the amount to developsymptoms.Many workerswho had experiof past and presentanimal contact and noting any encedanimal-associated rhinitis gave negative results history of respiratory symptoms,asthmaor hay fever in the skin tests.In addition, it was not p,ossibleto wascompletedby 213 volunteers.Of these,179were predict susceptibleindividuals on the basisof their classedas ‘handlers’who were engagedin full-time responseto the standardbattery of allergensalthough animalhusbandry,or ‘users’,thosewho usedanimals atopic individuals were more likely to develop aniexperimentally.Subjectswerealsoaskedabout symp- mal-related asthma.The authors consideredit untomsfrom animalcontact. Skin-prick testswere used likely that attemptsto screennew entrantsto identify to establishallergicresponses and atopic individuals potential suffererswould be successful and suggested wereidentifiedby a positive responseto one or more that future effortsshouldmainly be directedto reducof six commonenvironmentalallergenssuch as tree ing exposure. pollen and housedust. Reactionsto skin-prick tests with serumand urineextractsfrom rats, mice,guineapigs. rabbits and sheepwere assessed. In addition, serafrom the subjectswere testedby double gel dif- Methyl chloride and behaviour fusionagainstantigensfrom the five animalspeciesat 1mg/ml and the enzyme-linkedimmunosorbentassay Putz-Anderson. V., Setzer, J. V.. Croxton. J. S. 8c techniquewasusedon the sera. Phipps, F. C. (1981).Methyl chloride and diazepam
Food additives and contaminants-Fd Chem. Toxic. effectson performance.Stand. J. Work Enoir. Hlfh
PVC-inhaling
Vol. 20, No. 1
rats
141
again
7, 8.
It hasbeenreported that methyl chloride produces subtle but quantifiable behavioural effects at levels below the current TLV of 1OOppm.Repko et a/. (NIOSH Technical Information Publ. No. 77-125, 1976)found that 122workersexposedto a meanconcentration of 34ppm methyl chloride showed impaired performanceon cognitive time-sharingtasks and increasedfinger tremor although there was no detectable increase in the incidence of abnormal neurological symptoms compared with controls. However Hake et al. (Toxic appl. Pharmac. 1977,41, 198)exposedvolunteersrepetitively on a daily basis to methyl chloride concentrations of 20, 100 and 150ppm for periodsof 1, 3 or 75 hr with no deleterious neurologicalor behaviouraleffects.Put%Anderson et al. (cited above) sought to clarify the behavioural effectsof acuteexposureto permissiblelevelsof methyl chloride and to investigatethe effectsof concomitant administrationof diazepam(Valium).It was thought possible that any behavioural effects of methyl chloridemight be aggravatedby a central nervous systemdepressantsuchasdiazepam. Volunteersaged 18-32 were randomly assigndd -to six groups,four groupsof 12 and two groupsof eight. Each volunteer took a capsuleeither of 10mg diazepam or of a placebo30min beforeexposurefor 3 hr to 0. 100or 200ppm methyl chloride in the air. Only professednon-usersof diazepamwere askedto participate and they were all required to abstain from caffeine, alcohol and medical treatment for 24 hr beforeexposure.The three behaviouraltestsof visual vigilanceand dual-taskand time-discriminatingabilities wereusedto assess different aspectsof attention or alertness,during the 2 hr prior to treatment and during the 3-hr treatment period. Alveolar breath sampleswere taken ho.urly and blood sampleswere takenjust beforeexposureand about 90min after the start of exposure. Diazepamproduceda significanteffect in all of the beh9vioural tests resulting in an average decline of lO.lo/:, in performance compared with controls. Methyl chloride treatmentat the highdoseresultedin a marginally significant(47;) decline in performance. (The low-dosemethyl chloride groups were not includedin the statisticalanalysesbecauseof their small group sizes-eight/group.) The effect of the two treatmentscombinedwasadditive but not synergisticproducing a total reduction in performanceof 13.5%.As. expectedbreath and blood levels of methyl chloride were highly correlated but there were considerable inter-individual variations in body burden within groupsexposedto the samelevel. Hake et al. (lot. cit.) had found a similarly high degree of variation betweenindividuals. [Although this study indicatesthat acute exposure to permissiblelevelsof methyl chloride doesnot have marked behavioural effects the usefulnessof such resultsin determiningthe effectsof chronic exposure in the workplaceis not clear-cut.It may also be relevant that the onset of neurological symptoms in severemethyl chloride poisoningis delayed possibly for 24-48hr (Repko & Lasley, CRC Crir. Rec. Toxico/. 1979.6 (4). 283).]
Richards,R. J., Rose,F. A., Tetley, T. D.. Cobb, L. M. 8c Hardy, C. J. (1981).Effects in the rat of inhaling PVC dust at the nuisancedust level (10mg/m’). Archs envir. Hith 36, 14. Studiesto assess the degreeof hazard arisingfrom the inhalation of polyvinyl chloride (PVC) dustshave yielded inconclusive results. Suspensionhomopolymer PVC dust sampleshave proved to have little if any haemolyticaction in vitro, while paste(emulsion) polymer PVC dusts containing surfactantsproduce extensive red blood corpuscle (RBC) damage (Richardset al. Nature, Lond. 1975,256, 664; idem ibid 1976,260, 53).The surfactant wasconsideredresponsiblefor this activity (idem ibid 1976,260, 53), and for the toxicity to rat peritonealmacrophagesin vitro (Cited in F.C.7: 1981, 19, 277). In rats single intratrachealinstillationsof 2 or 20mg suspension or paste polymer PVC dust produced no progressive fibrogenic response(ibid 1980, 19, 277), but single intratracheal dosesof 25mg (unspecified)PVC dust have been shown to induce biochemicaland histopathological changesin rat lung tissue (Agarwal, Enuir. Res. 1978,16, 333).An earlier study had producedevidenceof granulomatousfoci in the lungsof guinea-pigsexposedcontinuouslyfor 2-7 monthsin a PVC baggingplant (Frongia et al. Medna Lao. 1974, 65, 321).and therehave beenisolatedreportsof pneumoconiosisin PVC workers (e.g. Arnaud et al. Thorax 1978,33, 19; Szendeet al. Medna Lou. 1970, 61, 433). However, a further study of 509 men who worked in a PVC-coated-fabricsand wall-coveringsfactory. someof whomhad beenexposedto PVC dust for over 15yr, showedno significantdeterioration in lung function (Cited in F.C.T. 1981,19, 512). Richardset al. (cited above) carried out a study to determinewhether the inhalation of a pastepolymer PVC-7 (containingthe detergentsodiumdodecyl sulphate) at ‘nuisance’dust levels(10mg/m3; Guidance Note EH 15/77, Health and Safety Executive, London, 1977)would produceany alteration in the lungs of experimentalanimals. Eighty lo-wk-old female albino Sprague-Dawley CD rats wererandomly allocated to either a control group or a PVC-exposedgroup (40 rats in each).The PVC-treatedanimalswereexposedto a meanconcentration of 10.6mg dust/m’ for 6 hr/day, 5 days/wk for up to 15wk. Groups of 10 exposedrats were examined and comparedwith control animalsat 3, 9 and 15wk. One group of animalsexposedfor 15wk was maintainedfor a further 15wk with no further contact with PVC and then examinedwith a non-exposed control group alsomaintainedduring this period. The lungsshowedsmall,randomly scatteredlesions after 15wk of exposure.Theselesionswere characterized by hypercellularity of the interstitium of the alveolar wallsin areasadjacentto macrophageaggregatescontaining numerousPVC particles.While the lesionspersisted15wk after the cessationof exposure, there were only minimal increasesin collagen and reticular fibre formation, and no evidenceof an extensive fibrotic reaction. Relatively few biochemical changesweredetectedat any exposureperiod.Three significant changesin cats exposedto PVC were (1)
Food additivesandcontaminants-FdChem.Toxic.Vol. 20,No. I
died or were killed (when moribund) and various Of the 179exposedsubjects31%(55)gave a history organs, including the entire gastro-intestinaltract of asthmaand/or,hay fever and 397”(70)were classed as atopic. Among the small group of non-exposed wereexaminedfor tumours. Tumours developedin go”/:, of the germ-freerats subjects357; wereclassedasatopic. Forty-nine, (27%) and 94”/”of the conventional rats with averagelatent of the exposedsubjectshad symptomsrelating to aniperiods of 11.7 and 13.7 months respectively. The mal contact, most commonly rhinitis but sometimes averagenumbersof tumours were 4*6/germ-freerat alsoasthma,and rashesand local urticaria often foland 4.4/conventionalrat. Apart from three germ-free lowedanimalscratchesor contact with urine or paws. rats with caecaltumoursall of the intestinal tumours The symptomsin most caseswere relatively minor were located in the distal part of the ileum. Of the but they occasionallypreventedfurther contact with germ-freerats six had ileal adenomas,three had cae- animals.There was no overall tendency for the more cal adenomas.one had an adrenocortical adenoma heavily exposedhandlersto have more allergicsympand nine had sarcomas. Of the conventionalrats eight toms than the usersalthough handlersdid develop hab ileal adenomas,ten had iliac adenocarcinomas, symptomsmore quickly than users.There wasno asone had a papillomaof the urinary bladder, two had sociationbetweenskin-test atopic status and sympadrenocorticaladenomasand five had iliac sarcomas. toms from animal contact with the exception of The sarcomasof germ-free rats were larger. more asthma.Subjectswith a previous history of asthma numerousand more rapidly growing than those of were more likely to develop animal-relatedasthma conventional rats. The non-intestinal tumours were but no morelikely to developother symptoms.Smokone adrenocorticaladenomain a germ-freerat and ing history wasnot relatedto symptomsfrom animal two adrenocortical adenomas and one bladder contact. Of the 179exposedsubjects29 had a positive reaction.to at leastone of the animal extracts after tumour in conventionalrats. There was no apparent difference betweengerm- 15min and this skin reactivity was positively associfree and conventional rats in tumour incidence ated with a history of symptomsfrom animal contact althoughthe absenceof gut microflora wasassociated although most of this associationwas due to the with a shorter latent period, increasedsusceptibility strongassociationbetweenskin reactivity and asthma to sarcomasand reduced susceptibility to adeno- from animal contact. Skin reactivity to animal carcinomas.The authorssuggestthat thesedifferences extracts was also associatedwith skin-test atopic were relatedto somedegradationof the bracken car- status. No precipitins were detected in the sera of cinogenby the gut microflora in conventionalrats. subjectsby gel diffusion against the animal extracts. [In view of the smallnumbersof animalsinvolved The enzyme-linkedimmunosorbentassayshowedno and the absenceof a control group theseresultscan significant differences in IgG levels between the variousgroups. only be regardedasa preliminary indication.] The authorsconsideredthat their resultsmay have Laboratory animals-turning the tables? underestimatedthe total number of allergy sufferers especially since many of the workers had only Cockcroft. A., Edwards.J.. McCarthy. P. & Anders- recently joined the units and may not have experison.N. (1981).Allergy in laboratory animal workers. enced symptoms,whilst the worst casesmay have given up working with animals completely. This Ltrncer I, 827. secondfactor may have had quite a significanteffect Nearly 32,000peoplework with laboratory animals sinceLutsky & Neuman(Ann. Allergy 1975.35, 201) in the UK and symptomsof allergy. particularly rhi- found that 28:; of the workers who were allergic to in the USA subsenitis and asthma,seemto be quite common. Many animaldanderin 39 establishments more peopleare exposedto animalsin different situ- quently changedjobs or avoidedcontact with specific ations and there have beena number of reports of animalspecies. Only five individualsshowedskin reactivity in the allergic reactions(includingone to elephants!). Cockcroft er al. have investigatedthe extent and absenceof symptomssuggestingthat skin tests are nature of the animal allergy problem in three MRC unlikely to be usefulasa prescreenfor peoplelikely establishments. A questionnairedetailing the amount to developsymptoms.Many workerswho had experiof past and presentanimal contact and noting any encedanimal-associated rhinitis gave negative results history of respiratory symptoms,asthmaor hay fever in the skin tests.In addition, it was not p,ossibleto wascompletedby 213 volunteers.Of these,179were predict susceptibleindividuals on the basisof their classedas ‘handlers’who were engagedin full-time responseto the standardbattery of allergensalthough animalhusbandry,or ‘users’,thosewho usedanimals atopic individuals were more likely to develop aniexperimentally.Subjectswerealsoaskedabout symp- mal-related asthma.The authors consideredit untomsfrom animalcontact. Skin-prick testswere used likely that attemptsto screennew entrantsto identify to establishallergicresponses and atopic individuals potential suffererswould be successful and suggested wereidentifiedby a positive responseto one or more that future effortsshouldmainly be directedto reducof six commonenvironmentalallergenssuch as tree ing exposure. pollen and housedust. Reactionsto skin-prick tests with serumand urineextractsfrom rats, mice,guineapigs. rabbits and sheepwere assessed. In addition, serafrom the subjectswere testedby double gel dif- Methyl chloride and behaviour fusionagainstantigensfrom the five animalspeciesat 1mg/ml and the enzyme-linkedimmunosorbentassay Putz-Anderson. V., Setzer, J. V.. Croxton. J. S. 8c techniquewasusedon the sera. Phipps, F. C. (1981).Methyl chloride and diazepam
Food additives and contaminants-Fd Chem. Toxic. effectson performance.Stand. J. Work Enoir. Hlfh
PVC-inhaling
Vol. 20, No. 1
rats
141
again
7, 8.
It hasbeenreported that methyl chloride produces subtle but quantifiable behavioural effects at levels below the current TLV of 1OOppm.Repko et a/. (NIOSH Technical Information Publ. No. 77-125, 1976)found that 122workersexposedto a meanconcentration of 34ppm methyl chloride showed impaired performanceon cognitive time-sharingtasks and increasedfinger tremor although there was no detectable increase in the incidence of abnormal neurological symptoms compared with controls. However Hake et al. (Toxic appl. Pharmac. 1977,41, 198)exposedvolunteersrepetitively on a daily basis to methyl chloride concentrations of 20, 100 and 150ppm for periodsof 1, 3 or 75 hr with no deleterious neurologicalor behaviouraleffects.Put%Anderson et al. (cited above) sought to clarify the behavioural effectsof acuteexposureto permissiblelevelsof methyl chloride and to investigatethe effectsof concomitant administrationof diazepam(Valium).It was thought possible that any behavioural effects of methyl chloridemight be aggravatedby a central nervous systemdepressantsuchasdiazepam. Volunteersaged 18-32 were randomly assigndd -to six groups,four groupsof 12 and two groupsof eight. Each volunteer took a capsuleeither of 10mg diazepam or of a placebo30min beforeexposurefor 3 hr to 0. 100or 200ppm methyl chloride in the air. Only professednon-usersof diazepamwere askedto participate and they were all required to abstain from caffeine, alcohol and medical treatment for 24 hr beforeexposure.The three behaviouraltestsof visual vigilanceand dual-taskand time-discriminatingabilities wereusedto assess different aspectsof attention or alertness,during the 2 hr prior to treatment and during the 3-hr treatment period. Alveolar breath sampleswere taken ho.urly and blood sampleswere takenjust beforeexposureand about 90min after the start of exposure. Diazepamproduceda significanteffect in all of the beh9vioural tests resulting in an average decline of lO.lo/:, in performance compared with controls. Methyl chloride treatmentat the highdoseresultedin a marginally significant(47;) decline in performance. (The low-dosemethyl chloride groups were not includedin the statisticalanalysesbecauseof their small group sizes-eight/group.) The effect of the two treatmentscombinedwasadditive but not synergisticproducing a total reduction in performanceof 13.5%.As. expectedbreath and blood levels of methyl chloride were highly correlated but there were considerable inter-individual variations in body burden within groupsexposedto the samelevel. Hake et al. (lot. cit.) had found a similarly high degree of variation betweenindividuals. [Although this study indicatesthat acute exposure to permissiblelevelsof methyl chloride doesnot have marked behavioural effects the usefulnessof such resultsin determiningthe effectsof chronic exposure in the workplaceis not clear-cut.It may also be relevant that the onset of neurological symptoms in severemethyl chloride poisoningis delayed possibly for 24-48hr (Repko & Lasley, CRC Crir. Rec. Toxico/. 1979.6 (4). 283).]
Richards,R. J., Rose,F. A., Tetley, T. D.. Cobb, L. M. 8c Hardy, C. J. (1981).Effects in the rat of inhaling PVC dust at the nuisancedust level (10mg/m’). Archs envir. Hith 36, 14. Studiesto assess the degreeof hazard arisingfrom the inhalation of polyvinyl chloride (PVC) dustshave yielded inconclusive results. Suspensionhomopolymer PVC dust sampleshave proved to have little if any haemolyticaction in vitro, while paste(emulsion) polymer PVC dusts containing surfactantsproduce extensive red blood corpuscle (RBC) damage (Richardset al. Nature, Lond. 1975,256, 664; idem ibid 1976,260, 53).The surfactant wasconsideredresponsiblefor this activity (idem ibid 1976,260, 53), and for the toxicity to rat peritonealmacrophagesin vitro (Cited in F.C.7: 1981, 19, 277). In rats single intratrachealinstillationsof 2 or 20mg suspension or paste polymer PVC dust produced no progressive fibrogenic response(ibid 1980, 19, 277), but single intratracheal dosesof 25mg (unspecified)PVC dust have been shown to induce biochemicaland histopathological changesin rat lung tissue (Agarwal, Enuir. Res. 1978,16, 333).An earlier study had producedevidenceof granulomatousfoci in the lungsof guinea-pigsexposedcontinuouslyfor 2-7 monthsin a PVC baggingplant (Frongia et al. Medna Lao. 1974, 65, 321).and therehave beenisolatedreportsof pneumoconiosisin PVC workers (e.g. Arnaud et al. Thorax 1978,33, 19; Szendeet al. Medna Lou. 1970, 61, 433). However, a further study of 509 men who worked in a PVC-coated-fabricsand wall-coveringsfactory. someof whomhad beenexposedto PVC dust for over 15yr, showedno significantdeterioration in lung function (Cited in F.C.T. 1981,19, 512). Richardset al. (cited above) carried out a study to determinewhether the inhalation of a pastepolymer PVC-7 (containingthe detergentsodiumdodecyl sulphate) at ‘nuisance’dust levels(10mg/m3; Guidance Note EH 15/77, Health and Safety Executive, London, 1977)would produceany alteration in the lungs of experimentalanimals. Eighty lo-wk-old female albino Sprague-Dawley CD rats wererandomly allocated to either a control group or a PVC-exposedgroup (40 rats in each).The PVC-treatedanimalswereexposedto a meanconcentration of 10.6mg dust/m’ for 6 hr/day, 5 days/wk for up to 15wk. Groups of 10 exposedrats were examined and comparedwith control animalsat 3, 9 and 15wk. One group of animalsexposedfor 15wk was maintainedfor a further 15wk with no further contact with PVC and then examinedwith a non-exposed control group alsomaintainedduring this period. The lungsshowedsmall,randomly scatteredlesions after 15wk of exposure.Theselesionswere characterized by hypercellularity of the interstitium of the alveolar wallsin areasadjacentto macrophageaggregatescontaining numerousPVC particles.While the lesionspersisted15wk after the cessationof exposure, there were only minimal increasesin collagen and reticular fibre formation, and no evidenceof an extensive fibrotic reaction. Relatively few biochemical changesweredetectedat any exposureperiod.Three significant changesin cats exposedto PVC were (1)