¦S^S:i Genetic hazards to man from environmental agents By David A.E. Shephard, FRCP [C] "Genes
. A large number of chemicals in seemingly side of a daily use have been recognized as being coin tossed many times during a re¬ mutagens a growing number of cent international symposium on gene¬ them are mutagenic in mammals in tic hazards to man from environmental vivo and some of them in man. This fundamental question how agents.* The other side of the coin: many of the myriad chemicals in our to balance the benefits of useful chem¬ environment induce genetic mutations, icals against the risks of their use and mutations, more often than not, was implicit throughout this sympo¬ are harmful rather than beneficial. sium, which brought together scientists Moreover, if, as many geneticists be¬ from the United States, Mexico, Great lieve, our genes are our most treasured Britain, Germany, Sweden, Italy and heritage, any deterioration in the qual¬ the host country, Canada. The overt ity of our genes can only lead to a purpose of the symposium was twodeterioration in the quality of our lives. fold: to permit scientists to exchange This, in essence, is the price society information and ideas about the gene¬ must pay for convenience living: for tic hazards of the sea of chemicals that convenience foods, convenience domes- surrounds us and to create a basis for tic and industrial goods, convenience decision-making that is essentially po¬ how to protect the public drugs, indeed, for the convenience of litical our very way of life, so dependant on from undesirable exposure to environ¬ the whole chemical environment. Is the mental chemicals in particular. But a price worth paying, in view of the risks covert purpose was just as important: to make the public aware of the ha¬ involved? zards that concern the scientific com¬ Consider: . An appreciable proportion of munity now and will concern scientists hospital admissions reflect genetic dis- increasingly for the rest of our lives. We have ignored these hazards for too abilities. . There are more than 1500 in- long. Action based on understanding herited diseases with a simple mode of of the scientific evidence is overdue, mendelian inheritance that are pri¬ for the problems that face us today will undoubtedly become ever more marily caused by point mutations. . Among clinically recognizable complex during the remaining years of spontaneous abortions more than 35% this century. This report is a discussion are associated with chromosomal aberof the important issues raised during the Ottawa symposium. rations. . Among 10 000 newborns there is The recognition of mutagenesis by a mean of 50 babies with a chromo¬ chemicals is comparatively recent; it somal anomaly, and in approximately was just over 30 years ago when C. 37 of these the anomaly is due to a Auerbach (Great Britain), a much renew chromosome or a genome muta¬ vered participant at the symposium, tion. showed that mustard gas damaged . On the basis of the frequency of chromosomes. More and more chem¬ chromosomal aberrations among abort- icals thereafter were found to be muta¬ uses and newborns we can conclude genic, but the magnitude of the prob¬ that at least 1% of all human zygotes lem was not realized until the 1950s. manifest chromosomal anomalies. Then, as C. Ramel (Sweden) pointed out, methyl mercury pollution resulted not only in clinically evident tissue damage but also, both in animals and in man, in an increased incidence of International symposium: genetic hazards to man from environmental agents. Ottawa, May chromosome breakage and aneuploidy 26-28, 1975. Cosponsored by health protection in branch of Department of National Health and lymphocytes. Welfare; the Genetics Society of Canada; and More recently another widespread the International Association of Environmental Mutagen Societies. One of a series of interna¬ industrial chemical, vinyl chloride, has tional symposia organized to mark the centenary focused our attention on environmental of health protection in Canada. hazards. Now, vinyl chloride is not only Reprint requests to: Dr. D. Shephard, Box 8650, CMA House, Ottawa K1G 0G8. mutagenic but carcinogenic as well, so are
simplistic
important."
statement
This
was one
.
*
1460 CMA JOURNAL/JUNE 21, 1975/VOL. 112
that the threat becomes a double one. As another symposium participant, B. Ames (USA), has shown, carcinogens are in fact mutagens, so that there is a close link between mutagenicity and carcinogenicity. Furthermore, as several participants reminded those attending the symposium, at least 80% of can¬ cers are environmental in origin hence the emphasis on carcinogenicity as well as mutagenicity of environmen¬ tal agents. But we must go further; as H. Kalter (USA) told the participants, there is also a close relationship between teratogens and mutagens. The relations be¬ tween teratogens and mutagens are not easy to distinguish but we must learn about the complexity of such relations so that we can control complexities we recognize. For a start we can identify environmental agents that are teratogenic (Tables I and II); then, identification is the basis for action against what is now a triple threat. One basic problem, then, is that environ¬ mental agents, particularly chemicals, produce a complexity of hazards; any new environmental agent therefore must now be examined, at the very least, from three points of view car¬ cinogenicity, teratogenicity and (com¬ .
these two) mutagenicity. underlying this problem is a deeper one: in dealing with the numer¬ ous hazards in our environment, man seems too often to be one jump be¬ hind. No sooner had a virus, rubella, been identified as causing congenital malformations and attention directed to the search for viruses, than a drug, thalidomide, was belatedly recognized as inducing birth defects. Then, after we switched to a closer look at rela¬ tively simple drug-lesion relationships, we had to face a much more subtle relationship: the time-expanding, generation-separating effect of a drug like diethylstilbestrol (DES). Astonishingly, this drug given to a pregnant mother can cause clear-cell vaginal cancer years later in the mother's daughter, a point well emphasized by D.T. Janerich mon
to
Yet
(USA).
What is the lesson? Where at all pos¬
sible, we must avoid mutagens. As J.W. Drake (USA) has emphasized, chem¬ icals and environmental agents induce
In the treatment of shock and its pulmonary
complications
Solu-Medrol enough, soon
often enough, in pharmacologic doses
Dosage and Administration: In treating severe shock, there is a tendency in current medical practice to use massive (pharmacologic) doses of corticosteroids. (The anti-inflammatory activity of 1 mg of SoluMedrol is equal to 4 mg or more of hydrocor¬ tisone.) The suggested dosage of Solu-Medrol for se¬ vere shock is 30 mg/kg stat and repeated in four hours, if necessary. Therapy is initiated by administering SoluMedrol intravenously over a period of at least ten minutes. In general, therapy should be con¬ tinued only until the patient's condition has stabilized-usually not beyond 48 to72 hours. Solu-Medrol may be given by intravenous in¬ jection, by intravenous infusion, or by intramuscular injection. The preferred method for initial emergency use is intravenous injection. Cautions: The general precautions and contraindications to systemic corticosteroid ther¬ apy should apply to the use of Solu-Medrol. However, when used for medical emergencies, or in shock-like states, the possible lifesaving effects must be weighed against the possible undesired hormonal effects. In the treatment of shock, Solu-Medrol should beadjunctive to conventional supportive therapy such as fluid replacement, ete. Although adverse effects associated with high-dose short-term corticoid therapy are uncommon, peptic ulceration may occur. Supplied: In Mix-O-Vials containing Medrol (as methylprednisolone sodium succinate),40 mg, 125 mg, 500 mg, and 1 g vials with water for injection. References: 1. Wilson, J.W. (1972). Surg., Gynec. & Obstet., 734:675. 2. Janoff, A. (1964). Shock, p.93. 3. DeDuve.C. (1964). Injury, Inflammation and Immunity, p. 283.
THE UPJOHN COMPANY OF CANADA 865 YORK MILLS ROAD/DON MILLS, ONTARIO
mutations through a wide variety of mechanisms; therefore, it is most likely that generalized schemes to protect the public against mutagens will be pro¬ grams aimed at preventing exposure entirely.
Recognition of mutagens Not surprisingly, therefore, much of the symposium was devoted to a con¬ sideration of how we can avoid muta¬ gens. Two approaches are useful: mu¬ tagenicity testing,* and epidemiologic studies. Mutagenicity tests were mentioned by many speakers, but particularly use¬
ful were the contributions of F.J. de Serres (USA) and of Ames. de Serres reminded his audience that mutagens can be found among a wide variety of commonly used chemicals including food additives, cosmetics (e.g. hair dyes), household agents, pesticides, in¬ dustrial chemicals and drugs. Such a large number of potentially harmful environmental chemicals and many have not yet even been recognized as harmful means that a particular approach to testing is needed. Tests on whole animals have limitations with respect to sensitivity, time and money. Hence, the value of short-term tests using microbial assay systems: these offer a practical solution to the prob¬ lem of testing hundreds of chemicals rapidly and inexpensively. This ap¬ proach amounts to one of screening. Such short-term tests have been devel¬ oped in particular by Ames, who uses a test incorporating histidine mutants of Salmonella typhimurium and rat (or human) liver microsomes. Such tests are recommended for the screening of food additives, drugs and chemicals to which humans are at present exposed and for the routine screening of all new chemicals to which humans are likely to be exposed. Compounds giving a positive test result for mutagenicity should be considered potentially hazardous and then scrutinized for ben¬ efit, risk and the need for further test¬
ing by other, more time-consuming part of a three-tier system proposed by B. Bridges (Great Britain). Many other tests are being developed for screening, and their interest to physicians lies in their rationale preventive, rather than curative, medi¬ cine. As de Serres advocated, "shortterm tests should most properly be con¬ sidered assays for potential mutagenic activity in man and as a highly efficient mechanism both for screening large numbers of environmental agents and for establishing priorities for further methods
.
testing
needs,
in more
higher organisms." Man than ever, to keep his wits
about him, and tests such as those of Ames help him do so. W.O. Rohrborn (Germany) took a slightly different approach to testing. First, a variety of host-mediated assay systems would be used. Substances found mutagenic in such qualitative studies and of no benefit (or replaceable by nonmutagenic compounds hav¬ ing the same degree of benefit) should be either banned from the marketplace or at least declared potentially hazardous. Those found to be mutagenic but not replaceable should then be tested quantitatively in mammalian systems (preferably mammals whose systems are as similar as possible to man's). In the case of drugs, for example, muta¬ genicity testing would be an inherent part of initial investigations and would be continued during the first clinical trials. The other method of recognizing mutagens is epidemiologic. Of particu¬ lar value here were the contributions of J.R. Miller (Canada) and Janerich. Mil¬ ler pointed out that until perfect animal tests are available and until such time as no harmful agents pass through the defence walls of the placenta, "we are obligated to devote our time to the monitoring of newborns (and ideally, fetuses and embryos) for the presence of agents which might damage many hundreds or thousands of conceptuses." Various monitoring systems are in use, in different countries, including Can¬ ada, where, by 1974, data from five provinces were being entered into the
system.
The value of such surveillance sys¬ indicated by the observation that the Swedish system if it had been in operation in 1963 would have iden¬ tified thalidomide-induced abnormali¬ ties. Janerich, in addition to referring to the value of epidemiologic studies in ascertaining the relationship between maternally administered DES and the occurrence of vaginal cancer in female offspring, stressed the contributions epidemiologists can make to identifica¬ tion of those environmental agents that are mutagenic. He used as an tems is
example
a
recent
report
on
the study
of a cohort of 257 polyvinyl chloride workers. Even so, as Miller observed, astute clinical observations are fre¬ quently the initial clues to mutagenicity
(whether carcinogens or teratogens are involved), and good clinical medicine remains paramount in the recognition of clinically important mutagens.
Protecting the public **The Testing of Chemicals for Mutagenicity, Carcinogenicity and Teratogenicity, Ottawa, 1975, Department of National Health & Welfare.
1464 CMA JOURNAL/JUNE 21, 1975/VOL. 112
Scientists from the United States u«:*«:o j and Germany britain, bweden
r^*.**n+ ureat
j
^
discussed national strategies dealing with the next phase: protecting the pub¬ lic from exposure to environmental chemicals. Most relevant to Canada was the contribution of Ramel, perhaps because of some similarities in social, political and legislative areas in the two countries. In particular, Canadian legislation, one hopes, will follow
Swedish practice. The central Swedish law is
a 1973 are ha-
concerning products that zardous to health and to the environ¬ ment. Two items are of particular in¬ terest: first, any manufacturer, importer or vendor of chemical products is responsible for preventing ill effects from such products; second, authorities are empowered to intervene even on the mere suspicion that a chemical product is toxic. In other words, the burden of uncertainty as to the hazard of any product does not rest on the the public but on those who manufacture, import or sell it. Moreover, a manufacturer, importer or vendor must supply the authorities with all such in¬ formation relating to each product as is necessary in assessing the dangers the product presents to the public health or to the environment. A products control board decides what tests are required to assess chemicals for hazards, and in particular a scientific reference group advises on mutagenicity testing. The importance of such a group is reflected in the realization that the carcinogeni¬ city of vinyl chloride could have been detected by simple mutagenicity tests. As yet, however, there are no legislative requirements for mutagenicity testing. In Canada, legislation for the regula¬ tion of environmental chemicals is being prepared. Currently, there is no legal requirement for mutagenicity test¬ ing, although different branches of the Department of National Health and Welfare are, on their own initiative, testing various environmental chemicals for mutagenicity as well as carcino¬ act
genicity. One of the department's re¬ presentatives, J.A. Abbatt, presented a useful and well-reasoned political view¬ point. In "the present state of igno¬ rance," Abbatt said, "decisions
be based
Human exposure: how much? The final session of the symposium was designed to take up this last point: to enable "authorities" to inform the public how much exposure is too much. F.C. Fraser (Canada) mused that this question was almost impos¬ sible to answer unless we were to say "less than an excess but more than not enough". CR. Scriver (Canada) em¬ phasized the view that a single guideline will not suffice, for every one is at some specific risk for a specific hazard, and there are wide individual variations related to genetic makeup. A certain exposure is too much for some but not too much for others. Other participants spoke more seriously on the vexing question of whether there is a threshold below which there is no damage, but this question, not surprisingly, was never fully answered. Bridges, however, made a telling point: at the level of DNA in the cell (the ultimate target of environmental agents) if there is mutagen, then some form of reaction is likely. J.A. Heddle (Canada) summarized this part of the
Tafcle I.Some drugs and other chemicals shown
to be teratogenic in species of laboratory mammal Type Examples Salicylates Aspirin, oil of wintergreen Certainalkatoids Caffeine, nicotine, colchicine Tranquillizers Meprobamate, chlorpromazine, reserpine istamines mor*
Un
Anesthetics Solvents Pesticides Mlscellaneous
(iliiilllilliiiilillll ¦iiliiil
lliiiliiiit
Source: Wiison's. Envkomnent and Brth de^
must
the best available scientific evidence" (much of which was pre¬ sented at the Ottawa symposium). Yet this, in the "less than perfect condi¬ tions" of the real world, is not enough. In balancing the benefits of environ¬ mental chemicals against their risks, it is up to society to decide what degree of risk is acceptable in achieving the degree of benefit desired. In short, the people, through their elected represen¬ tatives, must express what they want. But, at the same time, the public must be protected and they must be in¬ formed. on
one or
Hypo-and hyperthermia
Hypo-and hyperoxia
ijjl^ Mineral and trace element
symposium when he commented that the essential problem is estimating the amount of harm done by environmen¬ tal agents. He advocated taking a safe position, as far as dose and effect are concerned; that is, a dose-response curve should be regarded as being linear. Realistically, however, we have far to go in knowing where we stand. But there is much we do know, and this symposium particularly directed the attention of its participants to sep¬ arating fact from hypothesis. The fact is that many environmental chemicals are potentially mutagenic; therefore they are potentially dangerous. This symposium, which the health protection branch of DNH&W hosted, will expand our awareness of this fact. It will also point the direction in which medical thinking should be orientated a di¬ rection consistent with that of the 1974 working paper, "A New Perspective on the Health of Canadians". As Scriver pointed out, this document conceives the environment as being an important element in health care considerations. The constructive and enlightening Ot¬ tawa symposium supported in parti¬ cular the entirely reasonable view ex¬ pressed in "New Perspective" that "fu¬ ture improvement in the level of health of Canadians lies mainly in improving the environment. .." as well as in "moderating self-imposed risks and adding to our knowledge of human bio¬ logy". From this viewpoint, therefore, this international symposium on genetic hazards to man from environmental agents was highly successful; it was, in my
opinion, topical, enlightening,
con¬
structive and in tune with the future course of medical practice and with the good of society as a whole. ¦ CMA JOURNAL/JUNE 21, 1975/VOL. 112 1465
. A large number of chemicals in seemingly side of a daily use have been recognized as being coin tossed many times during a re¬ mutagens a growing number of cent international symposium on gene¬ them are mutagenic in mammals in tic hazards to man from environmental vivo and some of them in man. This fundamental question how agents.* The other side of the coin: many of the myriad chemicals in our to balance the benefits of useful chem¬ environment induce genetic mutations, icals against the risks of their use and mutations, more often than not, was implicit throughout this sympo¬ are harmful rather than beneficial. sium, which brought together scientists Moreover, if, as many geneticists be¬ from the United States, Mexico, Great lieve, our genes are our most treasured Britain, Germany, Sweden, Italy and heritage, any deterioration in the qual¬ the host country, Canada. The overt ity of our genes can only lead to a purpose of the symposium was twodeterioration in the quality of our lives. fold: to permit scientists to exchange This, in essence, is the price society information and ideas about the gene¬ must pay for convenience living: for tic hazards of the sea of chemicals that convenience foods, convenience domes- surrounds us and to create a basis for tic and industrial goods, convenience decision-making that is essentially po¬ how to protect the public drugs, indeed, for the convenience of litical our very way of life, so dependant on from undesirable exposure to environ¬ the whole chemical environment. Is the mental chemicals in particular. But a price worth paying, in view of the risks covert purpose was just as important: to make the public aware of the ha¬ involved? zards that concern the scientific com¬ Consider: . An appreciable proportion of munity now and will concern scientists hospital admissions reflect genetic dis- increasingly for the rest of our lives. We have ignored these hazards for too abilities. . There are more than 1500 in- long. Action based on understanding herited diseases with a simple mode of of the scientific evidence is overdue, mendelian inheritance that are pri¬ for the problems that face us today will undoubtedly become ever more marily caused by point mutations. . Among clinically recognizable complex during the remaining years of spontaneous abortions more than 35% this century. This report is a discussion are associated with chromosomal aberof the important issues raised during the Ottawa symposium. rations. . Among 10 000 newborns there is The recognition of mutagenesis by a mean of 50 babies with a chromo¬ chemicals is comparatively recent; it somal anomaly, and in approximately was just over 30 years ago when C. 37 of these the anomaly is due to a Auerbach (Great Britain), a much renew chromosome or a genome muta¬ vered participant at the symposium, tion. showed that mustard gas damaged . On the basis of the frequency of chromosomes. More and more chem¬ chromosomal aberrations among abort- icals thereafter were found to be muta¬ uses and newborns we can conclude genic, but the magnitude of the prob¬ that at least 1% of all human zygotes lem was not realized until the 1950s. manifest chromosomal anomalies. Then, as C. Ramel (Sweden) pointed out, methyl mercury pollution resulted not only in clinically evident tissue damage but also, both in animals and in man, in an increased incidence of International symposium: genetic hazards to man from environmental agents. Ottawa, May chromosome breakage and aneuploidy 26-28, 1975. Cosponsored by health protection in branch of Department of National Health and lymphocytes. Welfare; the Genetics Society of Canada; and More recently another widespread the International Association of Environmental Mutagen Societies. One of a series of interna¬ industrial chemical, vinyl chloride, has tional symposia organized to mark the centenary focused our attention on environmental of health protection in Canada. hazards. Now, vinyl chloride is not only Reprint requests to: Dr. D. Shephard, Box 8650, CMA House, Ottawa K1G 0G8. mutagenic but carcinogenic as well, so are
simplistic
important."
statement
This
was one
.
*
1460 CMA JOURNAL/JUNE 21, 1975/VOL. 112
that the threat becomes a double one. As another symposium participant, B. Ames (USA), has shown, carcinogens are in fact mutagens, so that there is a close link between mutagenicity and carcinogenicity. Furthermore, as several participants reminded those attending the symposium, at least 80% of can¬ cers are environmental in origin hence the emphasis on carcinogenicity as well as mutagenicity of environmen¬ tal agents. But we must go further; as H. Kalter (USA) told the participants, there is also a close relationship between teratogens and mutagens. The relations be¬ tween teratogens and mutagens are not easy to distinguish but we must learn about the complexity of such relations so that we can control complexities we recognize. For a start we can identify environmental agents that are teratogenic (Tables I and II); then, identification is the basis for action against what is now a triple threat. One basic problem, then, is that environ¬ mental agents, particularly chemicals, produce a complexity of hazards; any new environmental agent therefore must now be examined, at the very least, from three points of view car¬ cinogenicity, teratogenicity and (com¬ .
these two) mutagenicity. underlying this problem is a deeper one: in dealing with the numer¬ ous hazards in our environment, man seems too often to be one jump be¬ hind. No sooner had a virus, rubella, been identified as causing congenital malformations and attention directed to the search for viruses, than a drug, thalidomide, was belatedly recognized as inducing birth defects. Then, after we switched to a closer look at rela¬ tively simple drug-lesion relationships, we had to face a much more subtle relationship: the time-expanding, generation-separating effect of a drug like diethylstilbestrol (DES). Astonishingly, this drug given to a pregnant mother can cause clear-cell vaginal cancer years later in the mother's daughter, a point well emphasized by D.T. Janerich mon
to
Yet
(USA).
What is the lesson? Where at all pos¬
sible, we must avoid mutagens. As J.W. Drake (USA) has emphasized, chem¬ icals and environmental agents induce
In the treatment of shock and its pulmonary
complications
Solu-Medrol enough, soon
often enough, in pharmacologic doses
Dosage and Administration: In treating severe shock, there is a tendency in current medical practice to use massive (pharmacologic) doses of corticosteroids. (The anti-inflammatory activity of 1 mg of SoluMedrol is equal to 4 mg or more of hydrocor¬ tisone.) The suggested dosage of Solu-Medrol for se¬ vere shock is 30 mg/kg stat and repeated in four hours, if necessary. Therapy is initiated by administering SoluMedrol intravenously over a period of at least ten minutes. In general, therapy should be con¬ tinued only until the patient's condition has stabilized-usually not beyond 48 to72 hours. Solu-Medrol may be given by intravenous in¬ jection, by intravenous infusion, or by intramuscular injection. The preferred method for initial emergency use is intravenous injection. Cautions: The general precautions and contraindications to systemic corticosteroid ther¬ apy should apply to the use of Solu-Medrol. However, when used for medical emergencies, or in shock-like states, the possible lifesaving effects must be weighed against the possible undesired hormonal effects. In the treatment of shock, Solu-Medrol should beadjunctive to conventional supportive therapy such as fluid replacement, ete. Although adverse effects associated with high-dose short-term corticoid therapy are uncommon, peptic ulceration may occur. Supplied: In Mix-O-Vials containing Medrol (as methylprednisolone sodium succinate),40 mg, 125 mg, 500 mg, and 1 g vials with water for injection. References: 1. Wilson, J.W. (1972). Surg., Gynec. & Obstet., 734:675. 2. Janoff, A. (1964). Shock, p.93. 3. DeDuve.C. (1964). Injury, Inflammation and Immunity, p. 283.
THE UPJOHN COMPANY OF CANADA 865 YORK MILLS ROAD/DON MILLS, ONTARIO
mutations through a wide variety of mechanisms; therefore, it is most likely that generalized schemes to protect the public against mutagens will be pro¬ grams aimed at preventing exposure entirely.
Recognition of mutagens Not surprisingly, therefore, much of the symposium was devoted to a con¬ sideration of how we can avoid muta¬ gens. Two approaches are useful: mu¬ tagenicity testing,* and epidemiologic studies. Mutagenicity tests were mentioned by many speakers, but particularly use¬
ful were the contributions of F.J. de Serres (USA) and of Ames. de Serres reminded his audience that mutagens can be found among a wide variety of commonly used chemicals including food additives, cosmetics (e.g. hair dyes), household agents, pesticides, in¬ dustrial chemicals and drugs. Such a large number of potentially harmful environmental chemicals and many have not yet even been recognized as harmful means that a particular approach to testing is needed. Tests on whole animals have limitations with respect to sensitivity, time and money. Hence, the value of short-term tests using microbial assay systems: these offer a practical solution to the prob¬ lem of testing hundreds of chemicals rapidly and inexpensively. This ap¬ proach amounts to one of screening. Such short-term tests have been devel¬ oped in particular by Ames, who uses a test incorporating histidine mutants of Salmonella typhimurium and rat (or human) liver microsomes. Such tests are recommended for the screening of food additives, drugs and chemicals to which humans are at present exposed and for the routine screening of all new chemicals to which humans are likely to be exposed. Compounds giving a positive test result for mutagenicity should be considered potentially hazardous and then scrutinized for ben¬ efit, risk and the need for further test¬
ing by other, more time-consuming part of a three-tier system proposed by B. Bridges (Great Britain). Many other tests are being developed for screening, and their interest to physicians lies in their rationale preventive, rather than curative, medi¬ cine. As de Serres advocated, "shortterm tests should most properly be con¬ sidered assays for potential mutagenic activity in man and as a highly efficient mechanism both for screening large numbers of environmental agents and for establishing priorities for further methods
.
testing
needs,
in more
higher organisms." Man than ever, to keep his wits
about him, and tests such as those of Ames help him do so. W.O. Rohrborn (Germany) took a slightly different approach to testing. First, a variety of host-mediated assay systems would be used. Substances found mutagenic in such qualitative studies and of no benefit (or replaceable by nonmutagenic compounds hav¬ ing the same degree of benefit) should be either banned from the marketplace or at least declared potentially hazardous. Those found to be mutagenic but not replaceable should then be tested quantitatively in mammalian systems (preferably mammals whose systems are as similar as possible to man's). In the case of drugs, for example, muta¬ genicity testing would be an inherent part of initial investigations and would be continued during the first clinical trials. The other method of recognizing mutagens is epidemiologic. Of particu¬ lar value here were the contributions of J.R. Miller (Canada) and Janerich. Mil¬ ler pointed out that until perfect animal tests are available and until such time as no harmful agents pass through the defence walls of the placenta, "we are obligated to devote our time to the monitoring of newborns (and ideally, fetuses and embryos) for the presence of agents which might damage many hundreds or thousands of conceptuses." Various monitoring systems are in use, in different countries, including Can¬ ada, where, by 1974, data from five provinces were being entered into the
system.
The value of such surveillance sys¬ indicated by the observation that the Swedish system if it had been in operation in 1963 would have iden¬ tified thalidomide-induced abnormali¬ ties. Janerich, in addition to referring to the value of epidemiologic studies in ascertaining the relationship between maternally administered DES and the occurrence of vaginal cancer in female offspring, stressed the contributions epidemiologists can make to identifica¬ tion of those environmental agents that are mutagenic. He used as an tems is
example
a
recent
report
on
the study
of a cohort of 257 polyvinyl chloride workers. Even so, as Miller observed, astute clinical observations are fre¬ quently the initial clues to mutagenicity
(whether carcinogens or teratogens are involved), and good clinical medicine remains paramount in the recognition of clinically important mutagens.
Protecting the public **The Testing of Chemicals for Mutagenicity, Carcinogenicity and Teratogenicity, Ottawa, 1975, Department of National Health & Welfare.
1464 CMA JOURNAL/JUNE 21, 1975/VOL. 112
Scientists from the United States u«:*«:o j and Germany britain, bweden
r^*.**n+ ureat
j
^
discussed national strategies dealing with the next phase: protecting the pub¬ lic from exposure to environmental chemicals. Most relevant to Canada was the contribution of Ramel, perhaps because of some similarities in social, political and legislative areas in the two countries. In particular, Canadian legislation, one hopes, will follow
Swedish practice. The central Swedish law is
a 1973 are ha-
concerning products that zardous to health and to the environ¬ ment. Two items are of particular in¬ terest: first, any manufacturer, importer or vendor of chemical products is responsible for preventing ill effects from such products; second, authorities are empowered to intervene even on the mere suspicion that a chemical product is toxic. In other words, the burden of uncertainty as to the hazard of any product does not rest on the the public but on those who manufacture, import or sell it. Moreover, a manufacturer, importer or vendor must supply the authorities with all such in¬ formation relating to each product as is necessary in assessing the dangers the product presents to the public health or to the environment. A products control board decides what tests are required to assess chemicals for hazards, and in particular a scientific reference group advises on mutagenicity testing. The importance of such a group is reflected in the realization that the carcinogeni¬ city of vinyl chloride could have been detected by simple mutagenicity tests. As yet, however, there are no legislative requirements for mutagenicity testing. In Canada, legislation for the regula¬ tion of environmental chemicals is being prepared. Currently, there is no legal requirement for mutagenicity test¬ ing, although different branches of the Department of National Health and Welfare are, on their own initiative, testing various environmental chemicals for mutagenicity as well as carcino¬ act
genicity. One of the department's re¬ presentatives, J.A. Abbatt, presented a useful and well-reasoned political view¬ point. In "the present state of igno¬ rance," Abbatt said, "decisions
be based
Human exposure: how much? The final session of the symposium was designed to take up this last point: to enable "authorities" to inform the public how much exposure is too much. F.C. Fraser (Canada) mused that this question was almost impos¬ sible to answer unless we were to say "less than an excess but more than not enough". CR. Scriver (Canada) em¬ phasized the view that a single guideline will not suffice, for every one is at some specific risk for a specific hazard, and there are wide individual variations related to genetic makeup. A certain exposure is too much for some but not too much for others. Other participants spoke more seriously on the vexing question of whether there is a threshold below which there is no damage, but this question, not surprisingly, was never fully answered. Bridges, however, made a telling point: at the level of DNA in the cell (the ultimate target of environmental agents) if there is mutagen, then some form of reaction is likely. J.A. Heddle (Canada) summarized this part of the
Tafcle I.Some drugs and other chemicals shown
to be teratogenic in species of laboratory mammal Type Examples Salicylates Aspirin, oil of wintergreen Certainalkatoids Caffeine, nicotine, colchicine Tranquillizers Meprobamate, chlorpromazine, reserpine istamines mor*
Un
Anesthetics Solvents Pesticides Mlscellaneous
(iliiilllilliiiilillll ¦iiliiil
lliiiliiiit
Source: Wiison's. Envkomnent and Brth de^
must
the best available scientific evidence" (much of which was pre¬ sented at the Ottawa symposium). Yet this, in the "less than perfect condi¬ tions" of the real world, is not enough. In balancing the benefits of environ¬ mental chemicals against their risks, it is up to society to decide what degree of risk is acceptable in achieving the degree of benefit desired. In short, the people, through their elected represen¬ tatives, must express what they want. But, at the same time, the public must be protected and they must be in¬ formed. on
one or
Hypo-and hyperthermia
Hypo-and hyperoxia
ijjl^ Mineral and trace element
symposium when he commented that the essential problem is estimating the amount of harm done by environmen¬ tal agents. He advocated taking a safe position, as far as dose and effect are concerned; that is, a dose-response curve should be regarded as being linear. Realistically, however, we have far to go in knowing where we stand. But there is much we do know, and this symposium particularly directed the attention of its participants to sep¬ arating fact from hypothesis. The fact is that many environmental chemicals are potentially mutagenic; therefore they are potentially dangerous. This symposium, which the health protection branch of DNH&W hosted, will expand our awareness of this fact. It will also point the direction in which medical thinking should be orientated a di¬ rection consistent with that of the 1974 working paper, "A New Perspective on the Health of Canadians". As Scriver pointed out, this document conceives the environment as being an important element in health care considerations. The constructive and enlightening Ot¬ tawa symposium supported in parti¬ cular the entirely reasonable view ex¬ pressed in "New Perspective" that "fu¬ ture improvement in the level of health of Canadians lies mainly in improving the environment. .." as well as in "moderating self-imposed risks and adding to our knowledge of human bio¬ logy". From this viewpoint, therefore, this international symposium on genetic hazards to man from environmental agents was highly successful; it was, in my
opinion, topical, enlightening,
con¬
structive and in tune with the future course of medical practice and with the good of society as a whole. ¦ CMA JOURNAL/JUNE 21, 1975/VOL. 112 1465
