Meeting
of the British
Toxicology Society
of the British in held Edinburgh and Toxicology Society was organized jointly with the Faculty of Occupational Medicine, the Society of Occupational Medicine, and the Finnish Toxicology Society. This combination brought together persons with a particularly wide range of interests, and gave rise to some rewarding interactions, not only on a scientific, but also on a cultural and social level. The Meeting began with a teaching session on epidemiological statistics in which Dr Tomenson gave a very enlightening introduction to the basic concepts of epidemiology. We were gently introduced to cohort and case-control studies, standardized mortality ratios, compensations for age and birth date, odds ratios, proportional mortality ratios, and clusters. Some of us were rather surprised to learn that the ’healthy worker’ effect is considered to be a problem in epidemiology! However, by the end of the session we had been educated in at least some of the basic vocabulary of the subject, and enabled to appreciate both the strengths and weaknesses of the epidemiological approach. The
Autumn
1991
Meeting
was
Biological monitoring A main theme of the meeting was ’biological monitoring’, which may be defined as the determination of an individual’s exposure to a toxic compound. This may be achieved either by measurement of the concentration of the chemical or of its metabolite(s) in a biological fluid or tissue, or by the determination of a chemical or biological effect resulting from the exposure. Examples of the latter, covered at the meeting, are the chemical adducts formed by carcinogens with DNA or proteins, or the cytogenetic changes caused by these interactions. The coverage of biological monitoring at the meeting comprised a Teaching Session on its principles and practice in Finnish experience (Chair: Dr A. Vale), and a symposium on its applications in both UK and Finland (Chair: Dr P.B. Farmer). The second teaching session provided an excellent introduction to the subject. Dr A. Aitio, in a wide ranging survey, explained the advantage of biological monitoring, in contrast to the traditionally established methods of industrial hygiene, in determining the amount of absorbed compound in an exposed individual.
Interindividual variations in absorption, metabolism and excretion are all accounted for by the use of biological monitoring techniques. Translation of absorbed levels into health risks may (e.g. heavy metals, carbon monoxide) be possible, although in many cases dose-response data are not available, and biological monitoring measurements must be considered purely as an assessment of exposure. Analytical method development is of prime importance in biological monitoring as levels being measured are frequently close to analytical detection limits.
Cancer mutagens and toxic oil
syndrome
More than 90% of known human carcinogens (IARC Classes I, IIA, IIB) are known to be genotoxic (i.e. react covalently with DNA) and exposure to them may result in chromosome damage. Professor M. Sorsa reviewed the association between mutation, chromosome damage and cancer, and described the value of measurements of cytogenetic damage as a predictor of cancer risk. Structural chromosome aberrations (CA), sister chromatid exchanges (SCE) and micronuclei (MN) have all been used as indicators of lesions induced by genotoxins. Their relative sensitivity depends on the mechanism of interaction of the chemical with DNA. In recent model studies with several anticancer drugs the inter-laboratory reproductibility of these techniques has been confirmed. In an ongoing Nordic Prospective Study on Cytogenetic Endpoints and Cancer Risk suggestive evidence was obtained of the significance of CA to prospective cancer risk. The first key-note lecture was given by Professor W.N. Aldrige, who spoke about the Spanish toxic oil syndrome. This major toxicological incident first became apparent in May 1981. Although initially presenting as an acute respiratory illness, subsequent development of eosinophilia, muscle pain and muscle wasting, showed it to be a novel condition. Some 20 000 people became ill, and there have been 350 deaths. There was a clear epidemiological link between the syndrome and consumption of ’refined’ aniline-denatured rape seed oil, and oils linked to cases of the syndrome all showed rapeseed-derived constituents. In 1989 another new condition, eosinophilic myalgia, appeared in the USA. This was clinically similar to the toxic oil
Downloaded from het.sagepub.com at Purdue University on May 20, 2015
380
and resulted in 1536 cases by 1990, 27 of them fatal. A total of 37% of patients developed a sensory neuropathy. This time the causal agent was contained in impure 1-tryptophan derived from fermentation of 2-carboxyaniline. Although the primary toxins have not yet been identified, active research is being conducted in a number of laboratories.
syndrome,
Biological monitoring symposium The with
biological monitoring symposium opened a lecture by Dr G. Oliver on biological monitoring of exposure to plasticizers. Human exposure to plasticizers occurs extensively from water and medical devices. There is evidence of the carcinogenic potential of some plasticizers, although this is limited and is probably confined to rodents. Nevertheless, there is still an interest in obtaining individual exposure assessments to plasticizers in man. An exemplar
food,
compound di-(2-thylhexyl)adipate (DEHA), (present in PVC food wrapping films) was studied in detail. Following administration of deuterium-labelled DEHA to volunteers, metabolites were identified and analytical methods for them developed. The exposure to DEHA in a group of the general population was found to be of the same order as that estimated by MAFF from surveys of food and food-
wrapping materials. Dr K. Savolainen discussed the value of using biological monitoring methods for pesticides, using ethylenebisdithiocarbamates (EBDC) and an organophosphate mevinphos (MP) as examples. EBDC is metabolized to ethylene thiourea (ETU), a known thyroid carinogen, and the urinary concentrations of this were used as
indicator of EBDC exposure. The exposure by measuring cholinesterase activity and by assay of the urinary metabolite dimethyl phosphate. Skin absorption was suggested to be the most important route of exposure to MP. Cholinesterase measurements have the advantage of being directly related to toxic effects for organophosphates, while the relationship of metabolite level to toxicity varies. Metabolite assays are, however, often more sensitive. The association of polycyclic aromatic hydrocarbons (PAH) with cancer incidence is well known. Individual assessment of exposure to such compounds may be made by determination of the adducts formed between reactive PAH epoxide metabolites and DNA. Dr K. Vahakangas explained the use of three such methods (synchronous fluorescence spectrophotometry, ultrasensitive enzymatic radioiman
munoassay, and 32p-poSt labelling) to monitor workers at a coke oven in Finland. Air hydrocarbon levels and urinary 1-hydroxypyrene were also measured for comparison. Although the study is long-term, evidence has already been obtained of the value of adduct measurements in comparison, for example, to stationary air levels, for monitoring an individual’s exposure to PAH. Exposure to volatile halogenated hydrocarbons was described by Dr H.K. Wilson. The establishment of acceptable biological monitoring techniques for these compounds in an industrial setting requires data from well-controlled experimental exposures. These were provided using experiments using human volunteers exposed in an inhalation chamber to three halogenated solvents (chlorodifluoromethane, and 1,1,2-trifluoromethane 1,1,1-trichloroethane). Pharmacokinetic data for these exposures were used to suggest practical methods for monitoring occupational exposure. Interestingly performance deficits, associated with blood solvent levels, were apparent in the
trichloroethane-exposed population. The final lecture in the symposium was given by Dr P. Botham on laboratory animal allergies. Allergy to animals is a commonly occurring and an important problem for scientists and technicians working in biological sciences. Biological monitoring of such individuals, in conjunction with clinical diagnosis and laboratory environment monitoring is essential if the incidence of laboratory animal allergy is to be reduced. Dr Botham explained the use of such techniques and methods used to reduce exposure to animal allergies, in a successful attempt to reduce laboratory animal allergy at ICI.
Solvent
toxicity
to MP was assessed
There were 53 posters and six oral communications presented at the meeting, 14 of the posters relating to biomonitoring, and nine to solvent toxicity, which was the subject of the second symposium. Dr T5hti was the first speaker, and she described her work using the membrane bound enzymes acetylcholinesterase and ATPase to study solvent-protein interactions. This showed that whereas platelet ATPase was sensitive to a range of solvents, synaptosomal acetylcholinesterase (which binds to the outer surface of the membrane) was less sensitive. This and other results emphasized the importance of hydrophobic domains within proteins as sites for solvent interactions. Dr Gescher spoke about the hepatotoxicity of the formamides and nitroalkanes, solvents important in the ink and paint industries. He showed how cytochrome P450-
Downloaded from het.sagepub.com at Purdue University on May 20, 2015
381
linked metabolic activation could be related to the toxicity of the N-alkylformamides, but that in the case of the nitroalkanes the role of metabolism was far less clear. Dr Rühimäki then discussed the problem of interactions between ethanol and P450-linked solvent metabolism. This occurs at two levels, acutely when ethanol delays metabolic disposal by competition, and over the long term when enzyme induction predominates. Although many solvents are cleared at first pass by the normal liver, the induction by ethanol is sufficient to enhance the elimination of others, and also to increase the toxicity of those, such as the haloalkanes, which require metabolic activation. Dr Ray gave a brief review of organic solvent neurotoxicity, emphasizing the distinction between specific neurotoxicity such as that produced by hexane, methyl ~utyl ketone toluene and carbon disulphide, and less specific actions such as narcosis. He stressed the need to distinguish between reversible pharmacological and irreversible toxicological effects, and suggested that brain regional P450 isoenzymes and solvent-induced ototoxicity might provide useful areas for further research. Finally, Dr Cherry spoke about neurobehavioural responses to solvents and then, reverting to the theme of the first teaching session, emphasized the importance of epidemiology in the identification of solvent neurotoxicity. A
particularly striking example was the finding that an unexpectedly high proportion of Canadian psychiatric admissions showed a history of both solvent exposure and heavy drinking, suggesting a synergism between the two. It was interesting that most of the speakers in this session had stressed the practical and mechanistic signifiof interactions between solvents, and that between ethanol and other solvents. cance
particularly
Conciusion The meeting finished with the second keynote lecture given by Professor Tuomisto, who spoke about relative risk assessment in environmental and occupational toxicology. Drawing on a wide variety of data Professor Tuomisto suggested that minor health hazards from specific industrial and medicinal products were overestimated, whilst more global hazards, such as those originating from the use of motor transport, were underestimated. He then described the use of epidemiology in the assessment of cancer risk, giving examples of data collected from two rural communities in Finland.
Downloaded from het.sagepub.com at Purdue University on May 20, 2015
D. Ray P.B. Farmer
of the British
Toxicology Society
of the British in held Edinburgh and Toxicology Society was organized jointly with the Faculty of Occupational Medicine, the Society of Occupational Medicine, and the Finnish Toxicology Society. This combination brought together persons with a particularly wide range of interests, and gave rise to some rewarding interactions, not only on a scientific, but also on a cultural and social level. The Meeting began with a teaching session on epidemiological statistics in which Dr Tomenson gave a very enlightening introduction to the basic concepts of epidemiology. We were gently introduced to cohort and case-control studies, standardized mortality ratios, compensations for age and birth date, odds ratios, proportional mortality ratios, and clusters. Some of us were rather surprised to learn that the ’healthy worker’ effect is considered to be a problem in epidemiology! However, by the end of the session we had been educated in at least some of the basic vocabulary of the subject, and enabled to appreciate both the strengths and weaknesses of the epidemiological approach. The
Autumn
1991
Meeting
was
Biological monitoring A main theme of the meeting was ’biological monitoring’, which may be defined as the determination of an individual’s exposure to a toxic compound. This may be achieved either by measurement of the concentration of the chemical or of its metabolite(s) in a biological fluid or tissue, or by the determination of a chemical or biological effect resulting from the exposure. Examples of the latter, covered at the meeting, are the chemical adducts formed by carcinogens with DNA or proteins, or the cytogenetic changes caused by these interactions. The coverage of biological monitoring at the meeting comprised a Teaching Session on its principles and practice in Finnish experience (Chair: Dr A. Vale), and a symposium on its applications in both UK and Finland (Chair: Dr P.B. Farmer). The second teaching session provided an excellent introduction to the subject. Dr A. Aitio, in a wide ranging survey, explained the advantage of biological monitoring, in contrast to the traditionally established methods of industrial hygiene, in determining the amount of absorbed compound in an exposed individual.
Interindividual variations in absorption, metabolism and excretion are all accounted for by the use of biological monitoring techniques. Translation of absorbed levels into health risks may (e.g. heavy metals, carbon monoxide) be possible, although in many cases dose-response data are not available, and biological monitoring measurements must be considered purely as an assessment of exposure. Analytical method development is of prime importance in biological monitoring as levels being measured are frequently close to analytical detection limits.
Cancer mutagens and toxic oil
syndrome
More than 90% of known human carcinogens (IARC Classes I, IIA, IIB) are known to be genotoxic (i.e. react covalently with DNA) and exposure to them may result in chromosome damage. Professor M. Sorsa reviewed the association between mutation, chromosome damage and cancer, and described the value of measurements of cytogenetic damage as a predictor of cancer risk. Structural chromosome aberrations (CA), sister chromatid exchanges (SCE) and micronuclei (MN) have all been used as indicators of lesions induced by genotoxins. Their relative sensitivity depends on the mechanism of interaction of the chemical with DNA. In recent model studies with several anticancer drugs the inter-laboratory reproductibility of these techniques has been confirmed. In an ongoing Nordic Prospective Study on Cytogenetic Endpoints and Cancer Risk suggestive evidence was obtained of the significance of CA to prospective cancer risk. The first key-note lecture was given by Professor W.N. Aldrige, who spoke about the Spanish toxic oil syndrome. This major toxicological incident first became apparent in May 1981. Although initially presenting as an acute respiratory illness, subsequent development of eosinophilia, muscle pain and muscle wasting, showed it to be a novel condition. Some 20 000 people became ill, and there have been 350 deaths. There was a clear epidemiological link between the syndrome and consumption of ’refined’ aniline-denatured rape seed oil, and oils linked to cases of the syndrome all showed rapeseed-derived constituents. In 1989 another new condition, eosinophilic myalgia, appeared in the USA. This was clinically similar to the toxic oil
Downloaded from het.sagepub.com at Purdue University on May 20, 2015
380
and resulted in 1536 cases by 1990, 27 of them fatal. A total of 37% of patients developed a sensory neuropathy. This time the causal agent was contained in impure 1-tryptophan derived from fermentation of 2-carboxyaniline. Although the primary toxins have not yet been identified, active research is being conducted in a number of laboratories.
syndrome,
Biological monitoring symposium The with
biological monitoring symposium opened a lecture by Dr G. Oliver on biological monitoring of exposure to plasticizers. Human exposure to plasticizers occurs extensively from water and medical devices. There is evidence of the carcinogenic potential of some plasticizers, although this is limited and is probably confined to rodents. Nevertheless, there is still an interest in obtaining individual exposure assessments to plasticizers in man. An exemplar
food,
compound di-(2-thylhexyl)adipate (DEHA), (present in PVC food wrapping films) was studied in detail. Following administration of deuterium-labelled DEHA to volunteers, metabolites were identified and analytical methods for them developed. The exposure to DEHA in a group of the general population was found to be of the same order as that estimated by MAFF from surveys of food and food-
wrapping materials. Dr K. Savolainen discussed the value of using biological monitoring methods for pesticides, using ethylenebisdithiocarbamates (EBDC) and an organophosphate mevinphos (MP) as examples. EBDC is metabolized to ethylene thiourea (ETU), a known thyroid carinogen, and the urinary concentrations of this were used as
indicator of EBDC exposure. The exposure by measuring cholinesterase activity and by assay of the urinary metabolite dimethyl phosphate. Skin absorption was suggested to be the most important route of exposure to MP. Cholinesterase measurements have the advantage of being directly related to toxic effects for organophosphates, while the relationship of metabolite level to toxicity varies. Metabolite assays are, however, often more sensitive. The association of polycyclic aromatic hydrocarbons (PAH) with cancer incidence is well known. Individual assessment of exposure to such compounds may be made by determination of the adducts formed between reactive PAH epoxide metabolites and DNA. Dr K. Vahakangas explained the use of three such methods (synchronous fluorescence spectrophotometry, ultrasensitive enzymatic radioiman
munoassay, and 32p-poSt labelling) to monitor workers at a coke oven in Finland. Air hydrocarbon levels and urinary 1-hydroxypyrene were also measured for comparison. Although the study is long-term, evidence has already been obtained of the value of adduct measurements in comparison, for example, to stationary air levels, for monitoring an individual’s exposure to PAH. Exposure to volatile halogenated hydrocarbons was described by Dr H.K. Wilson. The establishment of acceptable biological monitoring techniques for these compounds in an industrial setting requires data from well-controlled experimental exposures. These were provided using experiments using human volunteers exposed in an inhalation chamber to three halogenated solvents (chlorodifluoromethane, and 1,1,2-trifluoromethane 1,1,1-trichloroethane). Pharmacokinetic data for these exposures were used to suggest practical methods for monitoring occupational exposure. Interestingly performance deficits, associated with blood solvent levels, were apparent in the
trichloroethane-exposed population. The final lecture in the symposium was given by Dr P. Botham on laboratory animal allergies. Allergy to animals is a commonly occurring and an important problem for scientists and technicians working in biological sciences. Biological monitoring of such individuals, in conjunction with clinical diagnosis and laboratory environment monitoring is essential if the incidence of laboratory animal allergy is to be reduced. Dr Botham explained the use of such techniques and methods used to reduce exposure to animal allergies, in a successful attempt to reduce laboratory animal allergy at ICI.
Solvent
toxicity
to MP was assessed
There were 53 posters and six oral communications presented at the meeting, 14 of the posters relating to biomonitoring, and nine to solvent toxicity, which was the subject of the second symposium. Dr T5hti was the first speaker, and she described her work using the membrane bound enzymes acetylcholinesterase and ATPase to study solvent-protein interactions. This showed that whereas platelet ATPase was sensitive to a range of solvents, synaptosomal acetylcholinesterase (which binds to the outer surface of the membrane) was less sensitive. This and other results emphasized the importance of hydrophobic domains within proteins as sites for solvent interactions. Dr Gescher spoke about the hepatotoxicity of the formamides and nitroalkanes, solvents important in the ink and paint industries. He showed how cytochrome P450-
Downloaded from het.sagepub.com at Purdue University on May 20, 2015
381
linked metabolic activation could be related to the toxicity of the N-alkylformamides, but that in the case of the nitroalkanes the role of metabolism was far less clear. Dr Rühimäki then discussed the problem of interactions between ethanol and P450-linked solvent metabolism. This occurs at two levels, acutely when ethanol delays metabolic disposal by competition, and over the long term when enzyme induction predominates. Although many solvents are cleared at first pass by the normal liver, the induction by ethanol is sufficient to enhance the elimination of others, and also to increase the toxicity of those, such as the haloalkanes, which require metabolic activation. Dr Ray gave a brief review of organic solvent neurotoxicity, emphasizing the distinction between specific neurotoxicity such as that produced by hexane, methyl ~utyl ketone toluene and carbon disulphide, and less specific actions such as narcosis. He stressed the need to distinguish between reversible pharmacological and irreversible toxicological effects, and suggested that brain regional P450 isoenzymes and solvent-induced ototoxicity might provide useful areas for further research. Finally, Dr Cherry spoke about neurobehavioural responses to solvents and then, reverting to the theme of the first teaching session, emphasized the importance of epidemiology in the identification of solvent neurotoxicity. A
particularly striking example was the finding that an unexpectedly high proportion of Canadian psychiatric admissions showed a history of both solvent exposure and heavy drinking, suggesting a synergism between the two. It was interesting that most of the speakers in this session had stressed the practical and mechanistic signifiof interactions between solvents, and that between ethanol and other solvents. cance
particularly
Conciusion The meeting finished with the second keynote lecture given by Professor Tuomisto, who spoke about relative risk assessment in environmental and occupational toxicology. Drawing on a wide variety of data Professor Tuomisto suggested that minor health hazards from specific industrial and medicinal products were overestimated, whilst more global hazards, such as those originating from the use of motor transport, were underestimated. He then described the use of epidemiology in the assessment of cancer risk, giving examples of data collected from two rural communities in Finland.
Downloaded from het.sagepub.com at Purdue University on May 20, 2015
D. Ray P.B. Farmer
