Will We Be Taught Ethics by Our Clones

1 Will We Be Taught Ethics by Our Clones? The Mutations of the Living, From Endocrine Disruptors to Genetics1 Published in Ethical Problems in Obstetric and Gynaecology, Claude Sureau and Françoise Shenfield (eds.) [email protected] International Practice and Research, Louise Vandelac, Ph.D. 2 with Marie-Hélène Bacon 3 Dominating our mastery “Henceforth there will be no scientific discipline which will not find itself facing the necessity of dominating the very mastery of the knowledge it possesses,” therefore it is important “to become not the masters of the world or the masters and owners of Nature, but rather the enlightened masters of our own power.” (Serres, 1995) This need for wisdom, prudence and responsibility towards the essence and integrity of humanity and our world, and towards the next generations and their future, has become more imperative than ever. Faced with the erosion in human health and intellectual faculties brought about by endocrine disruptors (related to organochlorines and persistent organic pollutants), with the test-tube-altered future of human conception and the industrialization of life, and with presumptuous projects to appropriate and engineer the living, and even to create new forms of life, this need has become an ethical imperative, and perhaps even a matter of survival... Indeed, given the frightening speed at which technological and genetic mutations of life are now occurring, ethics can no longer be content to simply address the ethical dilemmas linked to certain clinical problems, or to deal piecemeal with certain perverse side-effects 1 This paper was written with the help of a research grant from FODAR, (the provincial body of the University of Québec) entitled “Environmental Threats to Reproduction: the case for environmental and biomedical ethics.” This paper was also be inspired by a Social Sciences and Humanities Research Council of Canada grant for a comparative analysis of the press in France and Québec, 1984-1998, entitled “Reproductive Technologies, Media, Ethics and Democracy.” We thank those two research bodies for their financial support. We also thank Daphné Brunelle and Marc-Antoine Parent for their help with translation, and we thank Lou Nelson for her English revision of this text. 2 Full professor, Department of Sociology, and Searcher CINBIOSE, Université du Québec à Montréal. 3 Research assistant, Master's degree student. 2 introduced by technologies and the professional practices linked to them. Ethics for the Technological Age must become an Imperative of Responsibility, to paraphrase Hans Jonas (1984). In this article, we will see how the endocrine disruptor related to persistent organic pollutants (widely disseminated through uncontrolled chemical use during the past few decades) have begun to erode human health, human fertility and even intellectual faculties. This erosion is a very good illustration of our poor understanding of the complexity of the mechanisms of life, and our unbelievable pretensions to master the living. The endocrine disruptor may be an important alarm signal, forcing us to rethink our development and professional priorities and to focus instead on prevention and environmental and public health. It may force us to take a more global and integrated approach to science and ethics, one centred on a preventive and responsibility-driven approach that is more closely tied in with public and environmental health concerns. But there is a risk that, in a world increasingly dominated by computers and genetics, the presence of endocrine disruptors will be used instead to accelerate the technologization of the living and the mutations it engenders. In environmental health, inasmuch as most persistent organic pollutants (POPs) are pesticides, the temptation will be great to massively disseminate new genetically modified organisms, given the argument that we must urgently find alternative solutions to DDTs and other pesticides. Yet there is a risk that these solutions may be worse than the problems they are intended to address... In reproductive medicine as well, the temptation will be great to use the impact of endocrine disruptors as an argument to justify, for example, further recourse to ICSI ( intracytoplasmic sperm injection), and even for therapeutic purposes, cloning and ectogenesis, fuelling the reproductive and genetic engineering industries, unto foreseeable modifications in humans themselves. Life is xerox and I am just a copy... On June 30, 1998, in Paris... … in an interview with the daily newspaper, Liberation, the well-known geneticist Axel Kahn, one of the only scientists voicing opposition to human cloning in France, was defending the great medical interest in so called “therapeutic cloning” of the embryo, admitting however, that once it is accomplished, it will be very easy to create an adult human clone. In other words, he said, “the only reasonable chance of preventing the creation of human clones would be if it were technically impossible.” (Bensimon, 1998a:35). Is this not an eloquent avowal by the democratic bodies charged with protecting human dignity and liberty, and a cynical admission from an eminent member of the France Ethics Committee, of the impotence of ethics institutions confronted by this submission to the blind imperative of accomplishing what can be technically realized, despite the fact it is the very antithesis of ethical? That same day, on June 30, 1998, in Washington... 3 ...Maggie Fox, Health and Science Correspondent from Reuters reported that five days earlier, a team of researchers led by James Robl at the University of Massachusetts had developed a shortcut (using embryonic stem cells) which made the cloning and genetic engineering of cattle so much easier and so efficient4, that Neal First, of the Department of Animal Sciences, at the University of Wisconsin, in Madison, declared: “it is one of the more efficient things we’ve seen in terms of being able to make an animal. With this method, scientists will get their transgenic animal every time." In fact, in October 1997, a symbolic nine months before, two biologists at the University of Hawaii, Dr. R. Yanagimachi and Dr. T. Wakayama, had presented their results on the cloning of mice to the journal Science, which refused to publish them. That is why it was not until its July 21 issue that Nature reported the cloning of the first 22 mice (of more than 50 mouse clones), seven of which are clones of clones5 (Kolata, 1998). Considered by some biologists as "Dolly multiplied by 22," the implications of this work are for Dr. Lee Silver, a mouse geneticist and reproductive biologist at Princeton University, very clear: "Absolutely," he said, "we're going to have cloning of humans. If we follow scientific protocol," he added, "it could take 5 to 10 years before in vitro fertilization clinics add human cloning to their repertoires."(Ibid..) The protocol would require that the method first be perfected and shown to be safe in mice and then monkeys. "But that does not mean that somebody would not do it without those steps," he said (Ibid.). Axel Kahn claims to be opposed to embryo cloning for reproductive purpose and he stresses that if we clone an embryo for therapeutic purposes, we still face an ethical problem because it means that we are creating an embryo to make a medication instead of a human being, which means that we are reducing him to a pure object, one that is not related to a parental project anymore (Bensimon 1998:35). Even though the ethics of producing embryo for research is being discussed and contested, we must acknowledge that many countries are conducting such research and have done so for years. And this area of research holds the promise of major profits if genetic modifications and patent embryos achieve widespread acceptance. Is this why the Europe Council protocol adopted on January 12, 1998 proposes a clear prohibition against human cloning, but uses wording that implicitly authorizes the so-called "therapeutic" cloning of embryos? Endocrine disruptors: The threat POPs pose to health, intellectual faculties and fertility June, 30, 1998, in Montréal... While some people, pretending to be worried about clones, pave the way to the so called therapeutic cloning, and others are cloning cows and mice and already thinking about 4 This team used both a cloning technique known as a nuclear transfer, and a process in which embryos in a very early stage of development are “melded together,” to create 12 genetically engineered calf embryos, 9 of which carried an extra gene, which was introduced artificially. (Fox 1998) 5 Yanagimachi and his colleagues injected the cumulus cell's genetic material into mouse eggs whose own DNA had been removed. They waited six hours to give the egg a chance to reprogram the cumulus cell's DNA and then chemically prodded the egg to start dividing. All of the mouse clones were female. (Kolata 1998) 4 cloning humans, three hundred congress participants from 94 countries and many international bodies such as the United Nations Environment Program (UNEP) and the InterOrganization Program for the Sound Management of Chemicals, (FAO, WHO, UNIDO and OECD) were trying to save the world from what could be a nightmare: that of endocrine disruptors, a global threat to animal and human health and reproduction. Indeed and paradoxically, it was the same “clone day,” June 30 in Montreal, that UNEP organized the first meeting of the International Negotiating Committee (INC). After much pressure from physicians, scientists and environmental groups, this meeting was held to prepare an international, legally binding instrument which could initiate international action to ban and phase out the top twelve of numerous Persistent Organic Pollutants (POPs), called the "dirty dozen" (see Table 1). POPs are a group of mainly synthetic chemicals disseminated world-wide that are toxic to health. Some are also lipophilic and known to bio-accumulate in the tissue of animals and humans, and many persist in the environment. Of the contaminants which are absorbed, more than 90% are absorbed through food, for 2/3 through meat and dairy products (Health Canada:1997:124 ; Papke, 1998), and they are already found, on a large scale, in human tissues such as blood, milk and hair (see Table 2). These POPS have the potential to disrupt the endocrine system, whose actions aren’t limited to reproduction and development, but extend to all hormonal functions and could thus, for example, interfere with insulin production. These organochlorine chemicals can be divided into three categories: industrial chemicals such as polychlorinated biphenyls (PCBs) and Hexachlorobenzene (HCB); unintended by-products like dioxins and furans; and pesticides, such as aldrin, chlordane, DDT, endrin, heptachlor, dieldrin, toxaphene and mirex (Allsopp et al., 1998:1). To grasp the scale of what is involved, note that 400 million tons of up to 70,000 different chemicals are produced every year (UNEP, 1998). For example, three million tons of phthalates, a chemical used in Polyvinyl chloride (PVC) plastic and in food packaging, are used annually and end up in the environment (Greenpeace, 1997). Because dioxin is a byproduct of PVC, it is a very serious public health matter that we are surrounded by such materials, which are used in the most ordinary objects: children’s toys, pipes and water bottles, building materials, medical equipment and even wallpaper! (Ibid) Even though some contaminants have been banned in industrial countries, their production and sale in other countries has not been halted. For instance, DDT, an insecticide, banned since 13 years in North America, is still widely used in Asia, Africa and South America, mainly in agriculture and sanitation campaigns against malaria and the tsetse fly (Greenpeace, 1997: 3, Francoeur, 1998). A matter of life and health For decades now, numerous wildlife and laboratory studies have reported adverse reproductive and developmental effects, possibly mediated by endocrine disruptive pathways. Some of the major documented effects of various organochlorines on wildlife show disturbed fertility, masculinization or feminization, compromised immune systems, cancers of the female and male reproductive tract and altered sexual behaviour (Colborn, 1992 and 1996; Harrison et al., 1997, Crips et al.1998). These adverse trends in the 5 reproductive health of mammals, marine species, birds and fish parallel similar observations made, in recent years, of humans, meaning that these adverse effects are already occurring at the present chemical levels in our environment. Many of the observed human health effects are strikingly similar to those mentioned above for wildlife and laboratory animals. Sperm decline, endometriosis, breast, testicular and prostate cancers, immune disorders, neuro-behavioural problems and reproductive system impairments may be health problems resulting in particular from xeno-oestrogen exposure during in utero development, childhood, puberty and adult life. In the case of xenooestrogens, as we will see with neurological problems and male fertility impairments, the incidence, type and severity of the abnormality observed depends, among other things, on the developmental period during which the disruption of the normal endocrine balance occurred, as well as the duration of the disruption, because the timing of the exposure may have a greater impact on health than the dose itself. Although it is impossible to present a full overview of endocrine disruptor effects on human health, a few words must be said about two of the most widespread female diseases associated with endocrine disruptors: endometriosis and breast cancer. Endometriosis and breast cancer For endometriosis, there are still only few studies suggesting the role of endocrine disruptors (Gerhard, I et al. 1992 and Rier.SE et al. 1993 in Crisp et al. 1998), but this area of research is of presents a great interest given that this painful reproductive and immune disease affects between 7% and 10 % of women between the ages of 15 to 45, (5 million in the United States) (Holloway M. 1994), and often causes infertility, dysmenorrhea, and pelvic pain (Olive, DL and al. 1993). For breast cancer, several studies have presented enough evidence to support hypotheses linking oestrogen exposure and the rise in the breast cancer rate, though other causes such as ionizing radiation (Gofman in Crisp et al. 1998:7) cannot be dismissed. In any event, although there is still no clear cause and effect relationship, largely due to the complexities of research in the xeno-estrogen field, in a situation where breast cancer represents 30% of all cancers in Canada, more resources should be devoted to this area of research. Canada has the highest level of breast cancer after the United States, where breast cancer incidence rates rose by 24% between 1973 and 1991 (King-SE et Schottenfeld-D., 1996), and where it is estimated that 46,000 women will die of breast cancer in 1998 (Silverberg, 1988). Several studies conducted in the 1990s in Germany, Finland, Canada and the United States showed that women with breast cancer have substantially higher levels of lipophilic and environmentally persistent pesticides, such as organochlorines in their tissues (e.g., DDT and DDE6) (Wolff-MS et al 1993; Wolff-MS and Toniolo-PG1995; Crisp et al 1998:6 ), and that cancer risk and cancer mortality could rise with the level of exposure (Steingraber, 1997). In some studies, blood samples of women with breast cancer contained 35% more DDE, and 50% more lindane than the blood of healthy women, levels which put women in a situation where they are, respectively, four and ten times more likely to develop breast cancer (Ibid). 6 DDE is a breakdown product of oestrogenic pesticide o,p´-DDT which, as shown by Shekhar-PV et al. (1997), is the organochlorine with the most potent regulating effect on estrogen receptor-mediated cellular responses. 6 Furthermore, when Dewailly and colleagues studied oestrogen-receptor positive tumours, much higher DDE levels were found in women with oestrogen-receptor positive cancers than in the control group (Dewailly et al., 1994). Some critics contend that the rising level of breast cancer is due to earlier detection. This last factor might explain why the incidence rates are falling for later-stage diagnoses, but not why women born in the United States between 1947 and 1958 have almost three times more breast cancer than their greatgrandmothers at the same age, and why, as stressed by Steingraber, “the proportion of women developing the disease at all remains at the highest level ever recorded.” (Steingraber, 1997: 13,42). We must add that bioaccumulation of contaminants does not only put in jeopardy women’s health but also the one of their breastfed child. Is breastfeeding still so good for baby's health? Indeed an emerging body of information suggests that contamination has reached a level that may pose a large-scale, long-term public health risk and that breast-feeding contributes substantially to infants’ contamination. Years after chemical products have been banned in some countries, our bodies still carry the burden, which means that, mainly because of bioaccumulation, the exposure still remains . As shown in table 2, we are not talking here about a localized tendency but, tragically, an international one, as DDE contamination was found to be present in 100% of breast milk samples from across the world, in all studies but three, which reported it to be present in 96%, 97% and 99% of the samples, respectively. DDT was also reported in all countries, in proportions ranging from 21.5% to over 95% (Allsopp et al. 1998.) Further, and as evidence of the airborne transportation of these contaminants, several studies carried out since the 1980s among natives in Northern Québec show that PCB, DDE, mirex, HCB and chlordane levels are four to ten times greater in the breast milk of native women than of Canadian women living in the south. Despite the very important bond established between mother and their children during breast-feeding, some physicians are starting to wonder whether breast feeding might not prove to be a poisonous gift. Indeed, several studies show a decrease of dioxin levels in mothers’ milk with longer nursing periods and more breast-fed children (Fürst et al. in Papke, 1998). Milk being lipophilic, it stores contaminants and, as Hansen found with PCBs, 96% to 98% of PCBs 138, 153, and 180 are absorbed by infants from their mother’s milk (Hansen, 1998). The first months of lactation of the first child seem to be the most problematic, as levels of dioxin and PCBs in breast milk “...decreased by at least 12% per month during the first three months of breast feeding" (Lindstrom et al. 1994, Dahl et al 1995 in Allsopp et al.,1998:22). The amount of chemicals transferred to the child is modulated by the mother’s age, as her body burden increases every year 7, and by the number of breast-fed children, as her body burden decreases with each of them. Others studies (Schecter 1998, Abraham et al. 1994) support these observations and have shown without doubt that the mother’s body burden of chemicals decreases rapidly during lactation with a concomitant increase in the body burden of the child. 7 Studies and food surveys performed in industrialized countries have shown a median daily intake of PCDDs/PCDFs of 1 to 2 pg I-TEQ/kg/bw (Grün et al., 1995, Schrey et al., 1995). 7 An acknowledged daily overdose The body burden of breast-fed newborns increases rapidly, and as German studies reported, their daily dioxin intake is approximately 50 times higher than that of adults 8 (Fürst et al., 1992 in Papke:1998). It was also reported, in 1994 in Germany, that nearly all the PCDD/Fs and related compounds, including the I-TEQ9, were found to be about 10 to 15 times higher in the 11-month-old breast-fed infants than in the formula-fed infants (Abraham et al.,1994 in Papke, 1998). So, despite the fact that we are now aware of the occurrence of PCBs and other chlorinated compounds in mother's milk, and that breast-feeding is one of the main pathways for passing on contaminants from mother to infant, an expert group at the World Health Organization (WHO) meeting held in Geneva in May 1998 concluded paradoxically, as it did in 1988, in favour of the benefits of breast-feeding, thus maintaining the current dioxin ADI (acceptable daily intake) of 80pg/kg/bw (Ahlborg et al.,1992) for breast-fed infants ! At the same time, the current general ADI for the general population which was already 8 times less than for breast-fed infants, with 10pg/kg/bw for dioxins and furans, was reduced to 1 to 4 pg/kg/bw, a temporary aim as the goal of less than 1 pg/kg/bw10 is pursued.With 20 to 80 times more for breast-fed infants than for adults, it is thus a daily overdose, a shocking endowment that has a high risk of affecting and limiting a child’s capacities and possibilities for the rest of his or her life, as there is no way to counteract the effects of such overdoses11. Although WHO’s decision might be understandable in the case of countries where no other alternative is available, it remains highly problematic. As showed in three different studies, women with the highest levels of DDE in their milk had shorter periods of lactation, and had been able to breast-feed their children, especially their second or third children not even 40% as long as women with lower levels (Rogan et al.,1987; Clay Haynes: 1998). So high levels of DDE challenge women‘s capacity to breast-feed many children over long periods of time in countries and communities which often rely solely on it. Many women from India, Mexico and south Vietnam, for example, sharing one of the highest levels of chemicals in the world in their blood (Table 2), and facing the regular threat of starvation and an already high level of infantile mortality, are confronted now to this new Sophie's choice, which shows the gravity of the problem. Neurobehavioral impairments: a slow and subtle intellectual erosion The quantities involved during in utero exposure might be smaller than during postnatal exposure with breast milk, but are far more crucial, due to critical developmental stages the 8 Breast-fed babies consume on average 800 ml of milk daily, with a lipid content of 3%, which constitutes a daily dioxin intake of 77 pg I-TEQ/kg/bw for the nursing period. 9 International Toxicity Equivalents 10 Because each picogram of dioxin contains 1.88 BILLION molecules of dioxin, each of which is capable of disrupting a cell, many environmental and health activists have launched a campaign of letters to ATSDR calling on them to ratify the EPA limit of .006 pg/kg/day, or to set it to ZERO because, as they say, “many or most of us are near or at the 'limit' of harm”. 11 Since two-thirds of these contaminants come from dairy products and animal fats, it would be appropriate to suggest, when possible, that women alternate breastfeeding with formula feeding of babies, to reduce the toxic burden passed on to children. 8 foetus goes through, stages directed by sexual hormones that will influence its whole future, physiologically and intellectually. Indeed, an exposure to xeno-estrogens during these critical phases, even at doses as low as a few parts per trillion for a certain estrogenic chemical (Colborn, 1996), can cause permanent damage to developing nervous, reproductive, and immune systems. Even if our information comes mainly from acute poisoning accidents or controlled animal studies, relevant research on PCBs, dioxins and furans shows that the effects observed in wildlife and humans are consistent with the results of laboratory studies (Johnson et al.1998) and that the developing foetus or child is much more sensitive to adverse behavioural effects from toxic exposure than the adult (Riedel et al. 1997:152). Moreover, several studies which assessed the effects of prenatal exposure to PCBs, such as the North Carolina Cohort Study (Rogan et al. 1986; Gladen and Rogan 1991), which examined 856 breast-fed infants for up to 60 months, revealed that prenatal exposure to PCB was associated with neonatal hypoflexia and hypotonicity (Johnson et al.1998:24, Riedel et al. 1997), and concluded in no uncertain terms that there were neurobehavioral impairments. In the Michigan Maternal/Infants Cohort Study (Jacobson et al. 1984), prenatal exposure to PCBs was associated in a dose-dependent manner with lower body weight, poorer verbal skills and short-term memory than for unexposed children (Jacobson et al. 1990b). Even if prenatal exposure to PCBs seems more important than post-natal exposure in causing adverse effects in the central nervous system, hypo-activity was associated with concurrent levels of PCBs in the blood (Jacobson et al. 1990a in Riedel et al. 1997:93). The first replication and extension of the neonatal results of the Lake Michigan Maternal/Infant Cohort study by Lonky et al. (1996), who investigated 536 newborns of women who consumed Lake Ontario fish, concluded that neurobehavioral deficits occur at relatively low levels of fish consumption (Johnson et al.1998:17-18), i.e. in the group of women who consumed less than 40 pounds of Lake Ontario fish in their life. Subtle alterations in the nervous system function of adults aged 20 to 50 among Lake St. François fish eaters were also found by Mergler et al. (1997). These fish consumers scored significantly poorer results “on tests requiring cognitive flexibility, word naming, auditory recall, and more complex motor tasks ” (Mergler et al., 1997) and the declining speed of fine motor function could be a sensitive indicator of exposure (Schantz et al. 1997 in Johnson et al.1998:19)12. Lifetime consequences The neurobehavioral deficits do not fade away with time. The few follow-up studies of children exposed in utero leave no doubt, as Jacobson and Jacobson (1996) reconfirmed after their latest re-examination of 212 children of the Michigan cohort, that neuro-developmental deficits assessed in infancy and early childhood still persist at age 11 (Riedel et al.1997:93). The most highly exposed children had three-times lower than average IQ scores, were two 12 Despite the collective weight of evidence indicating that certain PCBs and dioxin-like compounds found in the fish in the Great Lakes-St-Lawrence River basins (and elsewhere) can cause neurobehavioral deficits (Johnson et al. 1998:4),the Canadian and American governments limit their actions to simply warning sport fish consumers of the dangers, when almost 80% of the subjects are eating their catch, and when it is estimated that half of the 4.7 million Great Lakes sport fish consumers are not aware of the safety guidelines issued by governments, and even then, in Barnegat Bay, NJ, 90% of the people still believed the fish and crabs were safe to eat (Tilden et al,1997, Burger J. et al., 1998). 9 years behind in reading comprehension, had poorer short and long-term memory, attention deficit, and were twice as likely to be behind in skills as unexposed children. These intellectual impairments, as in the case of lead, occur at concentrations of PCB congeners only slightly higher than those currently found in the general population (Johnson et al. 1998, Riedel et al.1997:107). It is important to keep in mind that these alarming consequences result solely from in utero exposure, and that those will be followed by breast-feeding exposure which, as shown in a Dutch PCB/Dioxin Study (Huisman et al. 1995), could also result in reduced neurological optimality (Johnson et al, 1998:26). Thus, enough evidence has been gathered to make it impossible to close our eyes on the fact that in the two-year period from 1993 to 1995, in Canada, 100% of the blood samples taken from the umbilical cord of Inuit newborns contained DDE, PCB and HCB and more than 90% of the samples contained oxychlordane and trans-nonachlore, and that the results for the non-Inuit newborns were largely similar, as DDE was found in 100% of the blood samples, and PCB and HCB in 90% of the samples (Jensen & al., 1997:359-360). Neurological deficits, “unlike budget deficits, cannot be repaid” (Jonhson et al., 1998:36) These compelling findings related to neurodevelopment and behaviour have been described as subtle, but their implications for future populations are huge. Thus, many authors and groups argue that it is not possible to recommend a tolerable daily intake of either total PCBs or of any individual congener, because among other things, both the RfD (reference dose) and the ADI (acceptable daily intake) (WHO) are based on the nonobserved-adverse-effect-level on adults (NOAEL) determined in the experimental animal model and they are not set for fetuses, pregnant women and children wich are much more sensible to adverse effects, and don’t take in account low-dose chronic exposure (Ahlborg et al., 1992). Considering the large variety of compounds involved and the complexity of their synergetic effects, in addition to the problem of bio-accumulation and the wide divergence in estrogenic responses, many suggest, faced with health problems of such serious consequences, and given the weight of evidence, that a precautionary approach be adopted. The application of the Principle of Responsability, to take the words of the philosopher Hans Jonas, would seem more appropriate to deal with these complex issues and to avoid to delayed the implementation of effective or at least preventive public policies. Reproduction endangered Forty years after DES was given to many pregnant women in order to prevent miscarriages, as was maintained by doctors at the time, we are just beginning to fathom how such an inefficient medication, a harmful exogenous estrogenic chemical (with anti-androgen properties), can affect the development of the human male and female reproductive systems, causing reduced fertility, increased rates of vaginal clear cell adenocarcinoma, various genital tract abnormalities, some changes in immune response, abnormal pregnancies, and a strong risk of ectopic pregnancy (Ankum et al. 1996) in the daughters; and for the sons: 10 reproductive tract abnormalities, genital malformations, epididymal cysts, testicular abnormalities, small testes, microphallus, triple or quadruple rates for cryptorachidism, and a significant decrease in sperm production (Colborn 1996; Gill et al.1979; Wilcox et al.1995). The effects of DES iatrogenics underline the potentially harmful effects of other chemicals with estrogen and anti-androgen properties, such as POPs, on embryos and foetuses exposed in utero. Sperm decline Even though many of the hypotheses associating DES and other environmental and occupational risk factors related to estrogens and anti-androgens have been advanced for years, it took the broad press coverage and world-wide controversy following the publication in 1992 of the Danish meta-analysis of Carlsen et al., which showed a significant 50% decline of human sperm density over the last 50 years13, before some scientists gave credence to the possibility that the decline in male fertility could be associated with environmental factors, an hypothesis already put forward in the mid-seventies. Confronted by such an “inconceivable” drop in sperm concentration, many researchers challenged the Carlsen study's conclusions on the basis of a variation in techniques or bias in methodologies (Brake and Krauss, 1992; Farrow, 1994; Olsen, 1995; Fisch, 1996a), or argued that the results were not consistent with other studies which found no change in semen parameters at multiple locations in France, the United States and Finland. (Bujan. et al., 1996; Fisch et al., 1996b; Paulsen et al., 1996; Vierula et al., 1996). Other scientists, having already begun research to prove the impossibility of such an important decline, were forced to concede, after analysis of the sperm counts and semen volume of first ejaculates provided by healthy fertile men volunteering as semen donors at Auger's Paris clinic from 1973 to 1992, that the sperm count seemed to decline by about 2.1% every year, which means that the count dropped from 89 million/ml to 60 million/ml during that interval ( Auger at al, 1995, Wright 1996). Recently, Becker and Berhane (1997) and especially Shanna H. Swan et al. (1997) conducted a complete reanalysis of the Carlsen work to try to resolve the controversy. Swan's study concluded that "the decline in sperm density reported by Carlsen et al. is not likely to be an artifact of bias, confounding, or statistical analysis" (Swan et al. 1997:8) 14. Even with large inter-area differences, a strong and significant decline in sperm density was observed overall in the United States (with an annual average decrease of 1.5 million sperm per milliliter of collected sample or 1.5% per year) and in Europe (3.1% per year), but was not observed in non-Western countries (where data were insufficient) (Ibid). So, more than ever research is needed (Jouannet P., Auger J.,1996 ). Without repeating the results of all the studies which shows a decline in the concentration and quality (motility and morphology) of spermatozoa (Auger et al. 1995; Irvine et al. 1996; Adamanpoulos et al. 1996; Ross, 1996; Van Waeleghem, 1996, De Mouzon et al. 1996), we 13 This meta-analysis of 61 studies, including 14,947 subjects from 20 different countries including the United States, Europe, Australia and some countries from South America and Africa, showed a drop from 113 to 60 million spermatozoids/ml between 1940 and 1992. 14 Swan et al. used data from 56 (of the initial 61) sperm density studies conducted between 1938 and 1990, showing that linear and nonlinear models gave similar results, 11 must acknowledge, and despite some differences in their findings and methodologies, a remarkable convergence, which is reinforced by the data from laboratory and wildlife research, increasing the collective weight of evidence regarding sperm decline and the estrogenic chemical role of some POPs in the adverse effects on male reproductive capacities, as shown by the elements presented below. First, the decline in spermatogenesis is accompanied by a significant rise in testicular cancer, which has climbed from 2% to 4% per annum since the 1960s, in Great Britain, the Nordic and Baltic countries, Australia, New Zealand, and the United States (Toppari et al. 1996). The fact that testicular cancer stems primarily from germ cells and affects primarily younger men (under 50 years of age), and because it is related to other anomalies of the male reproductive system (notably problems of cryptorchiditis or undescended testicles, as well as prostate cancer), supports the hypothesis of a disruption of the male endocrine system during development15. Second, Sharpe and Skakkebaek (1993: 1392-95) advance the hypothesis, basing themselves on the DES experiment and studies conducted on animals, that the decline in spermatogenesis and the rise in testicular cancer and other anomalies of the reproductive organs could be linked to exposure in utero to high levels of oestrogen, without excluding the risks of exposure in utero and during childhood and adulthood to other compounds which could equally compromise male fertility (Colborn, 1996: 176). Third, three studies (Auger et al., 1995; Irvine et al., 1996; Van Waeleghem et al., 1996) have pointed out that the younger a man is, the lower his concentration of spermatozoa and the higher the number of abnormal spermatozoa, which adds credence to the hypothesis of damage caused in utero (Colborn, 1996: 174-175). Thus, “whereas the concentration of the sperm of a Parisian man born in 1945 was one hundred and two million per ml, that of a man born in 1962 was exactly half that amount. Moreover, if this decline continues at the present rate, it will take 70 to 80 years to reach 0, Jouannet solemnly concludes.” (Wright, 1996:45). In fact, if these data are not related only to regional, or even local phenomena associated with specific environmental problems, such as lead for example, and if the tendency persists and nothing is done to curb its advance, we could reach the limit of 20 million, the threshold of natural fertility according to the WHO, in approximately 30 years. Until then, the proportion of men whose fertility is fragile, or even severely compromised, will probably become significantly greater. A horizon, then, of two or three generations seems quite close when the suspected origins of the problem are not only located at the heart of industrial development, but that many POPs also stay in the environment for many decades and are widely and frequently used in everyday life (Castleman, 1982, 1996). The scope and gravity of the demographic, geopolitical, and public health consequences of the fertility crisis associated with these POPs urges us to act. However, the great difficulty of "trapping," recycling, reducing and/or eliminating these estrogenic toxic contaminants, of which the “dirty dozen” represent only the tip of the iceberg (as shown in 15 Some evidence in epidemiological and animal studies show that environmental risk factors such as the heavy metal cadmium, and herbicides or PAHs may play a role in causing carcinoma of the prostate, an androgen-dependent organ (Crisp 1998). Prostate cancer is the second leading cause of cancer deaths in males in the United States, (with 200,000 new cases diagnosed in 1994, and 40,000 deaths, (172) representing an increase of 17% over the past 30 years despite the improvement in diagnosis) (Ibid). 12 Table 1), adds to the resistance of the powerful chemical industries (also involved in agribusiness and the pharmaceutical industry) to fully recognize the deleterious effects of endocrine disruptors on human health, which could be very costly. There is a very real threat that they could thwart and compromise the efficiency of public intervention, as was seen in the case of the Rio Summit resolutions or of the accords on greenhouse gas emissions, despite the very real risk posed to our collective future. 13 Where do we stand? From an ethical standpoint, the situation is as follows: On the one hand, we could take major steps to deal with the complexity of the situation with the urgency required, and, as a result, being responsible and using critical judgement, we could adopt the principles of caution, solidarity and concern for public health. This could lead us, individually and collectively, to reorient the premises, perspectives, priorities and even the policies of research in order to privilege early interventions in matters of the environment, of prevention and of education, and could also lead us to address therapeutic and palliative interventions from such a perspective. On the other hand, we could be sceptical, cynical and apparently impotent, and just as easily use the ill-considered “chemical momentum” of the past few decades to better justify the moves toward the technologization of conception and the “geneticization” of the living (Lippman, 1992). This could lead to the growth and widespread institution of a merchant or institutional economy of artificial reproduction (Vandelac 1990), which would gradually replace natural conception for wealthy populations in the Northern hemisphere. If the decline in sperm count is confirmed and amplifies, we may well be witness to a major increase in ICSI procedures and gamete donation, with the whole range of associated techniques and spectacular feats that it could engender (Vandelac 1996). We may also witness the proliferation of research on embryos, soon to be cloned, patented, genetically altered, or even used as a vector of cellular lines, thus giving the term “producer” a whole new meaning. This could also lead to major developments in ectogenesis, legitimized for so-called "therapeutic embryo cloning." And the alteration of the concept we have of human beings and humanity itself, an alteration which has already begun due to the technologization of conception, will be further amplified, giving an unprecedented depth to the mutation of human species (Hermitte, 1990 and Testart 1992a). In short, endocrine disruptors would not be the cause of all that but could be simply used as an easy justification. So to counteract the misdeeds and perverse effects left by the combined rule of the heavy and chemical industries, some, with a too-familiar assurance and unconcerned attitude toward long-term risks, will be tempted to accelerate the genetic modification and appropriation of the living. Indeed, considering the paucity of measures to impose caution and regulation, and the lack of information about the extremely complex mechanisms associated with the release of genetically modified organisms into the environment, solutions such as these run the risk of being worse in the end than the harm they are trying to repair. ICSI: between alpha and omega Still June 30, in Paris... In an interview with the daily newspaper Liberation, Bernard Jégou, Director of the INSERM Male Reproduction Study Group in Paris, firmly denounced the last ICSI experiment conducted by Japanese practitioner Sofikis, saying “It’s experimenting on humans!” (Bensimon, 1998b:31). He was responding to the practice of some researchers, who, when they don’t have a single spermatozoid, use immature cells like the spermatids (ROSI) and even spermatocytes taken directly from a fragment of testes (SESI). They then 14 fertilize an ova with two sets of chromosomes, which is one set too many, and aspire the surplus with a pipette, creating a hand-made genetic patrimony... (Ibid.) Jégou is one among so few scientists opposed to the premature and uncontrolled manner in which some technologies are disseminated in defiance of the usual rules governing experimental practices. He notes, dismayed, that “there have been no checks to assess the safety of the technique on animals, and not a shadow of an epidemiological study conducted on lineages obtained through this method.” One of the foremost researchers in France working on endocrine disruptors, Jégou is not slow to point out that developments using ICSI, ROSI and SESI are not exceptions, but rather excellent illustrations of how reproductive technologies have been developed since the beginning. Those reproductive technologies, he adds, “proceed from the "fait accompli," without concern for precautionary principles. The recent announcement in Cairo of a successful SESI is a biological coup. One more since Louise Brown.”(Ibid). The current rave for ICSI recalls the uncontrolled proliferation of in-vitro fertilization, equally experimental and inefficient, that has also been imposed through successive experimental breakthroughs in the past 30 years, (Corea, 1985; Vandelac, 1989) without adequate comparative studies on reliable experimental models (Testart, 1992b), and without rigorous scientific evaluation of its effectiveness (still under the 15% rate. FIVNAT, 1997; Marcus-Steiff, 1994), its safety and its risks for women and their children (Klein and Robin, 1988; Klein, 1989; W.H.O., 1990; Ste. Clair Stephenson , 1991; Relier, 1992; RCNRT, 1993; Laborie, 1994 a et b. etc. ). Why, then, this belated commotion about ICSI? Indignation of some searchers about uncontrolled ICSI-related practices is based mostly on the risk of transmission of genetic or chromosomic anomalies. Indeed, as pointed out by biologist Charles Thibault, somatic and germinal cells "use many common molecular mechanisms and, consequently, gamete anomalies may betray more general somatic-cell anomalies that may also be transmitted through ICSI." (Thibault 1998). None of this seems to dampen the enthusiasm. In France, the number of ICSIs multiplied by a factor of 137 in four years, going from 83 in 1992 to 11,400 in 1996! (FIVNAT 1997) This is more than half the 20,936 IVFs, even though less than two-thirds (62%) of ICSIs have been made for masculine indications (IBID). This speaks volumes about respect for the ethics of human experimentation! Worse, controversy seems to accelerate the process. First, by using molecular probes for genetic selection of male gametes, as suggested by Charles Thibault, to avoid the risk of transmission of chromosomic and genetic anomalies. Thus, such an ICSI-related tool for genetic selection could be used in the long term as a new instrument of positive eugenics, following the pre-implantation diagnosis (DPI), a diagnostic procedure which was loudly denounced in the book “Le désir du gène,” by biologist Jacques Testart (1992), who is, paradoxically, a promoter of ICSI and ROSI... Second, if we continue to search for ever more premature cells to ensure the “biologization of paternity” (Vandelac, 1988b), we pave the way to the legitimization of another kind of so-called “therapeutic” embryo cloning. As put by Axel Khan, “if the patient doesn’t produce any sexual cells, there will be a strong temptation to propose a child clone!” (Bensimon, 1998a: 35) 15 As Bill Gates' top technology officer, Nathan Myhrvold recently asked in an article for Slate, the Microsoft-owned online magazine, "What is so special about natural reproduction anyway? Cloning is the only predictable way to reproduce, because it creates the identical twin of a known adult. Sexual reproduction is a crap shoot by comparison -- some random mix of mom and dad." He followed this up by adding, "In any case, fear of clones is just another form of racism." (Paulsen, 1998). Need we add that Gates is enthusiastic about the future made possible by the marriage of computers and biotech. On the Microsoft Web site, he muses: "I truly believe that 20 years down the road, [researchers] will be using a combination of information technology and biotechnology to bring about a change in the human condition that will make anything we have done to date seem infinitesimal by comparison." 16 Conclusion "In the past, power meant land - control over what grew on it and what was extracted from it. Then power came to mean manufacturing - traditional industries. Today, power is life... and life is becoming the private ground of transnational and risk-capital investors". (Decornoy, 1992) How should we conceive of ethics when confronted to such an exorbitant power over life... over its production, its genetic engineering and patenting ? What is the power of ethics confronted by this new "embryo-economy of the living," its cloning, its transformation into tools of production and living manufacturers"? These far from marginal practices announce a major shift from an industrial society of wealth and services, embedded in the exploitation and transformation of natural resources, to a new bio-engineered and computerized society where life itself becomes the new energetic tool, fueled by the virtuality of financial capital, as clearly shown by Rifkin (1998). What forum is left to ethics and to democracy when the political power of the national states is increasingly subjected to transnational firms, and to such International commercial treaties as the Multilateral Accord on Investment (MAI) which are trying to replace national sovereignty by multinational ones? Although we cannot pretend to answer such large questions, we can reflect upon some of the ethical issues they raise. First, when the frontiers between humans, animals and plants are becoming permeable, as illustrated by xeno-grafts and genetic engineering of seeds, it would be wise to look again at the original definition of bioethics given by Potter (1968) as a global ethics of the living, beyond the more limited medical interpretation that has imposed itself since then. Environmental ethics and bioethics have a common ground and technoscience urges us to redefine a new bioethic paradigm, as shown by Hottois (1990) Second, when for private profit or to advance, without any limits, the frontiers of knowledge some people want to use body parts, reproductive organs and functions, cells and genes to appropriate and engineer the living, modifying in the process the very essence of humanity itself, ethical debates on such practices must be open to a broad base and cannot be left to a handful of experts. Ethics must become a new figure in politics, and impose a new ethics of politics. Third, ethics requires that we ask ourselves whether humans are entitled to do with themselves and to themselves everything they choose to do and everything they are able to do, when such doings could alter and compromise the future of other human generations (Decornoy, 1992). To put it more bluntly, we must ask whether it is “ethical” to allow market pressures and industry’s fantasies of omnipotence and illusions of omniscience, to redesign the human, human conception, and our concept of humans and humanity. If our answer is no, we must take the appropriate measures. In others words, not only must ethics take economic issues and stakes more into account, it must also impose a new ethics of economy. Fourth, reproductive and genetic technologies have already begun to change the nature and scope of medicine. For example, in the field of reproductive technologies, medicine deals less with pathologies or dysfunctions, than with the absence of conception, 17 which is falsely considered a pathology itself16. In such cases, medicine is no longer being asked for care, but for a child, and has thus been transformed into “supplier of potential children.” Does it mean that medicine could also, for infertility problem, go as far as to "propose a clone," to borrow the expression from Axel Khan? Reproductive medicine is changing the very meaning of a living being and of conception (de Vilaine et al, 1986; Labrusse-Riou, 1989). Thus, from the sexual and sexlinked semi-potential for conception, we are moving to the individual's “right” of “access to the conception of a child” through so-called “medical services,” as if procreation of a living being was a “service” of any kind, even medical! (Vandelac, 1995). By the same stroke, reproductive medicine, as the middleman in conceptions occurring over distances in time and space, the selector of breeding stock, the manager of gametes, the “producer” and controller of “the living being,” has also changed. Driven beyond itself, into the industrialization of life, the management of sexual relations and sexuality, and marked by an ominous tendency to trivialize the selection and soon perhaps the genetic engineering of our future descendants, this medical sector has wandered far from its primary mission to become a new factory for the production of “undifferentiated” living beings, some destined for birth and others merely to serve as objects of research or material for transplants, or cell lines ( Vandelac, 1996). That is why ethics must open new ethical perspectives for medicine and science. Neither analysis nor decisions can be left to scientists who are too often both judge and party. Fifth, the imposition of this new bio-power on bodies and the social fabric (Foucault, 1984) was aided and abetted by an incredible linguistic engineering which remodeled and bolstered our way of thinking (Vandelac, 1988b). In other words, wrapped in the deadening concept of progress, disguised as promoting choice, freedom and individual rights, reproductive technologies have served as the Trojan Horse, redefining Medicine, human conception, and human life from within the very bastion that should be protecting them. As Vandana Shiva17 showed in Biopiracy, her most recent book about genetic engineering and the political economy of seeds, the appropriation of resources and colonization of minds is always achieved by imposing a new rhetoric that legitimizes it. Comparing the piracy of European colonizers since the 15th century to the current biopiracy, the race of profit-minded gene hunters to patent every gene, cell line, tissue, organ and organism they can find, she says: “At the heart of Columbus's discovery was the treatment of piracy as a natural right of the colonizer, necessary for the liberation of the colonized. At the heart of the GATT treaty and its patent laws is the treatment of biopiracy as a natural right of Western Corporations, necessary for the development of Third World communities.(...)Through patents and genetic engineering, new colonies are being carved out (...) which are the interior spaces of humans bodies, plants and animals(...)It’s the ultimate colonization of life itself.(Ibid.: 4)”. 16 As pointed out by De Mouzon and Logerot-Lebrun (1992: 146) fertility problems are not “true” diseases, and artificial conception technologies, as Sureau adds, “can be considered elective practices since it is possible to live without offspring”(ibid). 17 Vandana Shiva is an Indian physicist who directs the Research Foundation for Science, Technology and Natural Resource Policy. 18 And we could add that at the heart of the appropriation and modification of the living is the "scientific right," under the guise of therapy, to use the very first and most fragile moment of human constitution, the embryo phase, as a simple tool, redefined as "preembryo," "surplus embryo," "therapeutic embryo cloning," and even "therapeutic cloning," from which even the word embryo disappears. So, one of our ethical tasks is to conduct an epistemological analysis and deconstruction of the discourses so often used to present these techniques as an evidence and even as a must. For example, the old notion of "progress" such as defined by Condorcet (1793) "as a general natural law conducting to the endless perfecting of the human species" (Condorcet, 1793 in Thuillier, 1995 ) had play and continue to play a key role. In the field of reproductive technology, such a "progress" has been like a train racing away and carrying us into ever more astonishing and disturbing terrain (its excesses appearing increasingly banal as the trip proceeds), until the departure station of infertility is lost behind us. Once we set out on this track, it seems that we cease to wonder why or how the train began its journey, who is driving it, what it is carrying or where it is headed. Moreover, few people have even seen it go by or are aware that it is literally changing the world. Sometimes poeple are struck and mystified by the breathtaking speed of the technological and genetic mutations reported in newspaper headlines, but these are presented as fabulous exploits. In such circumstances the train cannot be stopped, slowed down or redirected. At best, regulations are sometimes revised or, following public protests, some dangerous cars - but not always the most explosive - are removed, allowing the train to proceed even more rapidly (Vandelac, 1994 a). Now this train is taking us into the biotechnology world, a world where genetic discrimination and even categorization of new humans are taken for granted (Nelkin and Lindee, 1995). So, while a self-examination of the role of bioethicists would be welcome, a broad and democratic ethical debate must also take place to assess this future that some want to impose on others. Even for some it's seems already too late for protecting humanity against itself, we must confess thath when we are faced with the grave consequences of endocrine disruptors, we are in no position to say that it's too late and we have to be wise enough to rethink what we have done, to deconstruct our old ways of thinking and to assume our responsibilities. In the same way, when our identity, our integrity, and the future of our children are in jeopardy, could we pretend that is too late to reanalyse and even stop certain reproductive and genetic practices which have social consequences that are often far more problematic than the fertility problems themselves ? In recent years, many medical sonographers and pediatricians have argued against multiple transfers in IVF; many researchers have abandoned reproductive technology to reorient their work to environmental questions and/or fundamental research to prevent or cure fertility dysfunctions; many physicians and geneticist have analyzed the nature, scope and social implications of their work, creating professionals associations 18 to stimulate and intervene in the public debate. And I must add that many gynecologist and obstetricians are very conscious of the fragility and complexity of human conception and very attentive to these major transformations. But many of them are still being kept on this train by the 18 Such as the Council for Responsible Genetics (CRG) in the USA, Génétique et liberté (GEL) in France, Physicians for Social Responsibilities, heavily involved in the endocrine disruptor issue, and so on... 19 dynamic of supply and demand, and still hesitate to get off, slow down or reorient their own practice. As a society, if we continue to encourage the “splitting-and-marketing” of our gametes and our potential descendants; if we continue to erode the boundaries of the human species with the intent of abolishing all inter-species boundaries and genetically modifying the living in order to allow a few powerful people to appropriate it; in short if we continue, through indifference, and presumptuousness, to push ourselves outside of humanity, or at least out of our historical conception of it, then the question my seven-year-old son asked me this morning may be not only pertinent, but prophetic: "Mom, will humans disappear like dinosaurs did? List of Known & Suspected Hormone Disruptors Pollutants with Widespread Distribution Reported to have Reproductive and Endocrine-Disrupting Effects Persistent Organohalogens Dioxins and furans Octachlorostyrene PCBs Hexachlorobenzene PBBs Pentachlorophenol Pesticides 2,4,5-T DBCP h-epoxide oxychlordane 2,4-D DDT kelthane permethrin alachlor DDT metabolites kepone synthetic aldicarb dicofol malathion pyrethroids amitrole dieldrin mancozeb toxaphene atrazine endosulfan maneb ransnonachlor benomyl esfenvalerate methomyl tributyltin beta-HCH ethylparathion methoxychlor oxide carbaryl fenvalerate metiram trifluralin chlordane lindane metribuzin vinclozolin cypermethrin heptachlor mirex zineb nitrofen ziram Penta- to Nonyl-Phenols Bisphenol A and Phthalates Di-ethylhexyl phthalate Di-hexyl phthalate (DHP) (DEHP) Di-propyl phthalate (DprP) 20 Butyl benzyl phthalate (BBP) Dicyclohexyl phthalate Di-n-butyl phthalate (DBP) (DCHP) Di-n-pentyl phthalate (DPP) Diethyl phthalate (DEP) Styrene dimers and trimers Benzo(a)pyrene Heavy Metals Cadmium, Lead, Mercury Pollutants with Widespread Distribution Reported to Bind to Hormone Receptors and Therefore Suspected to have Reproductive and Endocrine-disrupting Effects 2,4-dichlorophenol, Diethylhexyl adipate Benzophenone, N-butyl benzene, 4-nitrotoluene SOURCES & NOTES: This list of substances was taken at http://198.53.192.127/hormonedisruptors/list.htm and is compiled from a variety of sources including: * Colborn, T. and C. Clement (1992) Chemically Induced Alterations in Sexual and Functional Development: The Wildlife/Human Connection. Princeton, NJ: Princeton Scientific Publishing. * Colborn, T., F. vom Saal and A.M. Soto. (1993) Developmental Effects of Endocrine-Disrupting Chemicals in Wildlife and Humans. Environmental Health Perspectives, Vol 101, Number 5. * Lyons, G. (1995) Phthalates in the Environment. World Wildlife Fund UK. * Ministry of Agriculture, Fisheries and Food. (1995) Effects of Trace Organics on Fish, Phase II, Foundation for Water Research, UK. All of the substances presently identified as hormone disruptors are now widely distributed throughout the environment, some are common constituents of consumer products, and many are now found in human tissues. Table 2 Summary of Mean Levels of Organochlorine Pesticides in Breast Milk on a Lipid Basis (ppm) Country p,p’DDT p,p’DDE Dieldrin HCB HE B-HCH g-HCH 0.96 0.159 0.411 0.061 0.345 Australia Victoria 0.225 Brazil Sao Paulo Porto-Algre 1.31 0.12 2.53 0.07 0.108 0.0344 0.02 0.02 0.9 0.02 21 Canada Czech Republic 0.0221 0.222 0.00978 0.998 0.0145 0.00377 0.0226 0.639 0.001 0.071 (sum) France Germany 0.044 2.183 0.38* 0.19 0.147 0.097 0.287 0.037 0.14* 0.223* 0.014 0.045 0.016 India Dehli Ludhiana Fairidkot Italy Jordan Kazakstan Kenya Mexico The Netherlands Nigeria Norway 7.18 10.0 8.83 2.31 13.81 12.85 4.37 0.21 8.20 0.41 0.15 2.2 0.18 0.45* 2.04* 0.05* 0.29* 0.3 1.96 nd 0.091 3.73 2.95 1.271 5.017 0.705 2.27 0.40 nd 0.047 0.013 2.210 0.23 0.561 0.022 0.083 1.33 0.338 0.041 (sum) Russia Kola Peninsula 5 different regions Slovak Republic Spain Sweden Thailand Turkey Mania, Van Kayseri UK USA 0.178 1.269 0.129 0.387 1.408 0.126 1.667 0.012 0.6041 0.03 0.35 0.731 3.610 0.1 2.01 0.41 2.389 0.0067 0.084 <0.02 0.40 0.03 0.02 0.08 0.023 0.541 0.026 0.022 0.020 0.002 <0.0023.0 0.245 0.0118 1.589 0.0094 0.0311 0.235 0.0105 0.829 0.0039 0.069 0.0008 0.037 0.02 0.007 0.119 0.003 0.05 0.011 0.522 0.156 <0.02 22 South Vietnam 4.70 6.70 0.004 0.003 0.221 0.023 Table2 shows a summary of information compiled by Allsopp et al. 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