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ON THE ESTIMATION OF THE GENETIC RISK FROM RADIATION
COMMENTING ON RESULTS FROM
GENETIC EPIDEMIOLOGICAL AND DOSIMETRIC STUDIES OF PEOPLE EXPOSED TO HIGH NATURAL RADIATION IN THE MONAZITE BEACH OF KERALA AND GENETIC STUDIES AT HIROSHIMA-NAGASAKI
Padmanabhan VT
Occasional Paper 2002/6 July 2002 Aberystwyth: Green Audit
1. GENETIC EPIDEMIOLOGICAL AND DOSIMETRIC STUDIES OF PEOPLE EXPOSED TO HIGH NATURAL RADIATION IN THE MONAZITE BEACH OF KERALA
In 1957, the World Health Organization appointed a committee to take stock of the then existing knowledge base on radiation induced genetic disorders in humans. Nothing much was known, though some three decades earlier, H. Mueller had demonstrated that his 20 kV X-ray machine could damage the genes of fruit flies (Drosophila Melanogaster), more efficiently than all other known chemical mutagens. WHO was responding to the growing demand by people, especially mothers, to stop the bomb testing. They were also supported by Nobel laureates like Mueller and Linus Pauling. Majority of the WHO committee members were convinced that low dose radiation is genotoxic. One of the medical radiologists in the committee even recommended treating medical X-rays on par to morphine.
One of the main recommendations of the committee was to undertake a long-term genetic epidemiological study in Chavara-Neendakra, a twenty-five-kilometer long coastal strip in Kollam (earlier Quilon) district of Kerala in Southwest India. This strip, an island with Arabian Sea to the West and a backwater-canal system to the East, has one of the largest natural deposits of monazite, which contains thorium, uranium and their daughters. The mean annual background radiation in the strip is 550 mRad/year, (range 240 - 3500 mR) as against 100 mRad/year in the normal areas. The coast has been inhabited by fisher-people for over twenty generations. The WHO committee noted that (a) the people were exposed to chronic low dose, which is comparable to the exposure situation of radiation workers and (b) there were communities, comparable in other respects, living in contiguous coastal areas with normal radiation. Two years later, WHO also prepared a detailed outline of the proposed study.
Responding to this development, the Bhabha Atomic Research Centre (BARC), the research wing of the Department of Atomic Energy set up a sophisticated cytology laboratory and initiated a series of research programs in the Kerala strip during the early sixties. This facility was closed in 1995. They studied the cytology of hundreds of blood samples of children and parents from the monazite strip and normal areas. However, not a single paper has been published in the open literature from this facility.
In a paper published in Nature (1975), researchers from the All India Institute of Medical Sciences (AIIMS), Delhi reported a statistically significant increase in Down's syndrome, severe mental retardation, abortion and chromosomal aberrations among 12,000 people in the monazite villages in comparison to 6,000 people in living in the normal area. BARC joined the debate, arguing that the excess was caused due to high maternal age, which has been refuted by the original authors. BARC finally agreed for a joint study, but this also did not materialize. The BIER report of 1990 dismisses this study as biased without offering any grounds. The radiation community has been quoting the example of people living in the Kerala monazite strip as healthy and unharmed, in spite of the chronic exposure, to prove that low dose radiation does not cause any harm to the genetic material.
We conducted a retrospective genetic epidemiological survey in the monazite strip and four coastal villages in Alapuzha (earlier Alleppey) district with normal background radiation during 1988-96. There were 38,000 people in the monazite villages (study area) and 32,000 people in the other four villages with normal background radiation (control area). The objective of the study was to see if chronic exposure to low dose radiation increases the chances of genetic abnormalities among the offspring.
Details of the Study
· Dosimetry. The external radiation was measured with a portable gamma counter at 700 points in the study area and 115 points in the control area.
· Thermo-luminescent Dosimeters (TLDs) were exposed in 98 households for one month. These were read at Stralhentelex, Berlin.
· Physical structure of the household. Height of floor from the ground, material used for flooring, ventilation and furniture in 125 households. The gamma dose was also measured in these households to estimate the shielding effect from the structures and furniture.
· Concentration of the radioactive elements was measured in four species fresh fish collected from the study and control areas and dried/baked in Kerala. The radionuclide concentration was measured at REKLIT, Amsterdam.
· Dietary intake of 25 households for seven days was recorded to study the possibility of internal exposure from locally grown/harvested food.
· Demographic Survey. Trained investigators canvassed a schedule eliciting socioeconomic and demographic information from 13,500 households in study and control areas.
· Details of 47,000 pregnancies among 13,000 mothers below 60 years.
· Medical examination of 15,000 persons reported to be suffering from an anomaly of interest, by a team consisting of doctors, nurses and research assistants. They recorded anthropometric measurements and antenatal history, details of infections and other events of significance of the subjects. Persons suffering from complex anomalies were re-examined by consultants, most of who were teachers in medical colleges.
· Chromosomal and DNA studies on peripheral blood of children suffering from complex syndromes involving mental retardation and their parents (total samples 156). The analysis was done at the All India Institute of Medical Sciences, (AIIMS) Delhi.
The main findings of the study area:
1. Dosimetry. The deposits being uneven, there is wide variation in readings between different parts of the study area. Usually, the readings were higher in the southern half. Likewise, the levels were lower in the eastern segments than the western ones close to the Arabian Sea. There was no difference between dose estimated from TLD exposure and readings from the gamma counter. Exposure was higher in houses with a lower floor height.
2. The concentration of radionuclides was higher than the maximum permissible limit in two species of fish.
3. Higher incidence of chromosomal disorders and dominant single gene anomalies among the children born to exposed parents, with an excess relative risk of 50% among the exposed population. All differences statistically significant.
4. The UNSCEAR has estimated the 'background' load of Mendelian anomalies from ad hoc surveys conducted in several Western cities. Their estimate and the estimated birth incidence in the control area in this series are almost similar.
5. Common congenital anomalies like mental retardation, deafness, blindness, cerebral palsy, clubfoot, polydactyly etc account for about 60% of the total caseload. Incidence of these disorders is higher among the children of the exposed parents, consanguineous couples and children whose grandparents were from the same village. This is indicative of their inheritance in a recessive mode.
6. Seventeen of the 18 Down syndrome children with a successful karyotype had primary trisomy, while the karyotype of one person showed translocation (14t-21).
7. A higher incidence of chromosomal aberrations (like fragile X) among the unaffected parents of the anomalous children in the study area in comparison to the unaffected parents from the control area.
The interim findings of the study were presented at the II International Radiation Victims Congress, Berlin, INTACH seminar on nuclear safety, Delhi and Saitama University Tokyo. The analysis was completed in 1998 and the paper has been with a couple of peer-reviewed subject journals. The stated reason for rejection has been that this goes against the findings in Hiroshima-Nagasaki and all the animal studies.
Advisory Support. Dr Rosalie Bertel guided the study team.
2. GENETIC STUDIES AT HIROSHIMA-NAGASAKI
Ionizing radiation has received more campaign, scientific and regulatory attention than all the other human-made toxins in our environment. However, the issue of health hazards to exposed persons and their descendants has not been resolved. The owners of the nuclear facilities, both the governments and the corporations, are currently trying to lower the risk estimate, in spite of the mounting evidence from studies with people exposed to low doses from Chernobyl and other releases. The proposed downward revision of risks will allow the operators to release radioactive material for civilian use and avoid the clean up of contaminated sites. Independent experts and environmentalists are fiercely opposing the revision. However, the question of genetic effects among the descendants of the exposed persons has not received any critical review from independent analysts so far.
The United Nation's Scientific Committee on Atomic Radiation (UNSCEAR) and the expert group on Biological Effects of Ionizing Radiation (BIER) of the United States National Academy of Sciences - the two main standard setting agencies- assert that radiation induced genetic effect has not been demonstrated in humans. While accepting the genotoxicity of radiation, these committees dismiss the reports of heritable anomalies among the offspring of radiation-exposed workers, veterans and general public as unscientific. According to them, the current exposure levels are too low to show any visible increase in genetic anomalies. Last year, the radiation community recommended an upward revision of genetic doubling dose from the existing 100 Rads to 500 Rads.
Both these committees rely heavily on the ongoing research among the Hibakushas in Hiroshima and Nagasaki. The Atomic Bomb Casualty Commission (ABCC) of the US army initiated the studies among the Hibakushas immediately after the bombings. In 1975, ABCC handed over its projects and assets to the Radiation Effects Research Foundation (RERF), which is a joint venture of the US Department of Energy and the Japanese Ministry of Public Health. The human health studies conducted by ABCC-RERF have a fairly large sample size, the survivors received varying doses (ranging from one rad to over 400 rads) and they are prospective in nature. Above all, these studies are expected to continue till the middle of this century. All other studies have smaller sample size and shorter follow-up. Because of these unique features, even critics like John Gofman, consider RERF studies as more reliable. However, there has been serious mismanagement of data at ABCC, which has lead to a serious under-estimation of the health risk, especially the genetic effects.
Types and sources of Exposures in and around the bombed cities
The survivors in the bombed cities were exposed different types of radiation from different sources, which are given below:
(a) Gamma rays and neutrons released during the explosions, which were instantaneous. The dose was the highest at the hypocenters. Distance from hypocenters, shielding and posture were factors, which influenced the dose.
(b) Neutron activation products (NAP). All stable elements in nature, including those in human body, were turned into radioactive isotope by the intense neutron emission from the bombs. Most of the activation products were short-lived, but there were also a few long-lived activation products like Zn54. The survivors themselves became radioactive, their bones had radioactive phosphorus. Besides the external radiation from the NAPs, there were also possibilities of internal exposure through the food chain, mainly from the rivers and reservoirs around the bombed cities. The survivors had made use of all usable materials for constructing their homes and truck gardens. In Nagasaki, the local residents informed Lt. R.E. Pace of US Navy that their truck gardens were more fertile after using the contaminated soil.
(c) Fission Products in the Black Rain. After the explosions, fission products were scattered far and wide in Japan. Koi-Takasu, off Hiroshima and Nishiyama, off Nagasaki were the prominent fall out regions. Physicians of Nagasaki medical fraternity reported monocytopenia and other complications among the populations exposed to the fall-out in Nishiyama. Both the fall-out areas were located beyond 2000 meters of the hypocenters.
Within a week of the bombing, Hiroshima was hit by a typhoon. A substantial portion of the activation and fission products could have been drained to the rivers around the city.
Exposure from (b) and (c) were chronic. Since the debris had long lived radionuclide like cesium, plutonium, uranium etc., exposure continues till day.
Dose Estimation at ABCC-RERF
Until the mid-fifties, the dosimetry was based on distance from the hypocenters and history of experiencing one or more of the acute radiation symptoms like loss of hair, bloody diarrhea etc. Those who were 2000 meters away from the hypocenters were said to have received 'negligible' dose. Initially, the unexposed control group constituted of persons who were beyond 10 kms from hypocenters at the time of bombings. This group was known as "Not-In-City At the-Time of-Bombing" (NIC-ATB). The NIC had two sub-cohorts, the first one consisting of the residents of the bombed cities who were away from the cities ATB for work or studies. They returned to the cities as early as they could. The other sub-cohort consists of migrants from rural Japan and repatriates from the overseas Japanese colonies like Korea and Manchuria. This group came in much later as reconstruction works were progressing. These groups were labeled as NIC Early Entrants (NIC-EE) and NIC Late Entrants (NIC-LE).
As radiation-induced leukemia became visible by the mid-fifties, there arose the need for a detailed dosimetry. Efforts at estimation of individual doses for the survivors were really elaborate. These included (a) shielding studies by interviewing the survivors regarding their posture, position and activity status ATB (b) Analysis of tiles and other materials from the bombed cities for estimating the dose from NAPs at Lawrence Livermore. (c) Two bombs, similar to the ones dropped at Hiroshima and Nagasaki were detonated at Nevada, with Japanese type houses, animals and phantom humans at varying distances from the hypocenters. (Well, in majority of these tests, there were also soldiers posted at a distance. And there were the Newadans further downwind.) In spite of these efforts, the dosimetry is still incomplete. The dosimetry is highly inadequate since it does not account for the NAPs and fission products in the fall-out mentioned in (b) and (c) above. Incidentally, there is sufficient published data on radiation levels at the hypocenters and main fall-out regions, until six months after the explosions. However, there is no data on contamination of the food chain in the open literature.
The radionuclides in the food chain would have affected all the residents more or less uniformly. At the same time, exposures to NAPs, mainly in and around the hypocenters and FPs in the fall-out regions were selective. NIC-Early Entrants were exposed to fairly high level of residual radiation from the NAPs. Many of the early entrants suffered from acute radiation symptoms and the Japanese government had, during the late sixties, extended the medical concessions of Hibakushas to NIC (EE) also. They constituted about 20% of the NICs in the master sample of ABCC. ABCC did not estimate the dose of these subjects. At the same time, they had provided the mortality data of NIC (EE) separately in a couple of their reports till the mid-seventies, which showed excess mortality due to cancer and other causes, which was comparable to the mortality rate of those in dose group 50-100 rads. (b) The residents of the intense fall-out areas, which were beyond 2000 meters from the hypocenters, were not excluded from the distally exposed subjects. Incidentally, NICs and distally exposed subjects were the unexposed control groups of ABCC. Inclusion of these highly exposed persons in the control groups, had obviously lead to a gross underestimation of the radiation risk.
Health Studies of ABCC-RERF
The human health studies of ABCC-RERF can be classified into (a) somatic and (b) genetic. In the former the endpoints are growth, morbidity and mortality of the exposed persons. In genetic studies, the same endpoints are sought in the offspring born after the exposure. During the initial days, those who were NIC-ATB were considered as the unexposed control group. Some scholars argued that the repatriates from Korea and Manchuria, who constituted more than 50% of the NIC, were richer than the permanent residents of the bombed cities. The formers also had a higher incidence of venereal diseases. Considering these, the ABCC decided to carve out an internal control consisting of the residents who were in the cities ATB, but beyond 2000 meters (The distally exposed group, whose estimated external dose was less than 1 rad as per DS86). In all the somatic studies, the distally exposed persons constitute the control group. In the genetic studies, both NIC and the distally exposed subjects (beyond 2000 meters from the hypocenters) are treated as the unexposed control group. Though the RERF has been collecting the mortality statistics of NIC group also, they have been withholding the same from their reports in since 1975.
Somatic Studies
The outcome under observation in the Life Span Study (LSS) is death from all causes. This is the most important ongoing research program. Initiated in 1950, LSS had 100,000 survivors who were within the cities and 26,000 persons who were NIC-ATB. This single largest death monitoring system in the world is expected to be in place for another four decades, till the death of the last Hibakusha. In 1955, LSS reported an increased risk of leukemia among the survivors. Since then, other solid tumors, some of them rare, started showing. As the risk of cancer per unit of exposure has been increasing in the subsequent analysis, UNSCEAR and BEIR have been recommending a reduction of permissible exposure of radiation to workers. There have been serious manipulations with the LSS sample, which have been exposed by John Gofman.
The Genetic Studies
Before the bombing, there were about half a dozen studies, which indicated exposure-linked genetic damage in humans. These studies revealed that there were more male children when the father was exposed and more female offspring when the mother was exposed. These were in line with the genetic hypothesis based on the findings in other species. After the bombings, the Japanese scholars concerned about the genetic effects of exposure started systematically assembling the data on pregnancy outcome among the exposed. At this juncture, Lt. J.V. Neil of the US Navy, the only military medical doctor with a Ph.D. in genetics, proposed to undertake a genetic study among the offspring born to the survivors, in order to 'consolidate the local Japanese efforts'. There was hardly any coordination between the Japanese scholars and ABCC. The formers published their findings in Japanese, which have been more or less ignored by ABCC and the standard setting agencies. Most of their reports are still inaccessible for the non-Japanese scholars.
ABCC's genetic study (GE-3 program), headed by J.V. Neil and W.J. Schull included about 76,000 born during 1948-53. Pregnant women of 20 weeks gestation were enrolled for the study at the time they were registering themselves for the subsidized rations. The end-points in the study were (a) prenatal loss after 20 weeks of gestation, (b) neo-natal death, (c) gross abnormalities, (d) birth weight and (e) sex ratio. The mid-way analysis of the study was done in 1951 and the report was submitted to the National Academy of Science. A brief summary of the report published in the journal Science, had a provocative sub-title, which indicated that the exposure has damaged the genetic material. There were excesses of abnormal and underweight babies among the offspring of the exposed, but these differences were not statistically significant. At the same time, there was a significant change in sex ratio (SR) of offspring of the exposed parents, which was in line with the genetic hypothesis and other human studies mentioned above. Considering the importance of the topic, ABCC decided to extend the study from 1954 to 1962 (SR study Phase II). There were 75,000 children in this phase also. In this phase, only the sex of the newborn were noted, no other examination was conducted.
The findings of GE-3 study (which includes SR Phase I also) and SR Phase II were published separately in the journal Science and also as RERF TR 7/81. There are five dose groups for paternal and maternal exposures viz., NIC, Less than 1 rad, 1-10 rads, 11-100 rads and above 100 rads. The 'less than 1 rad' consisted of distally exposed subjects who were beyond 2000 meters from the hypocenters. With five dose groups for fathers and mothers, there were 25 parental exposure groups. Both the NIC and the 'less than 1 rad' group have been used as the control subjects. The effect found in the first phase evaporated in this report. RERF dismissed the earlier observation as fortuitous. Their position now is that the 'extensive and expensive' genetic effects program did not yield any positive result.
Re-analysis of RERF Sex Ratio study
Sex Ratio Study (Phase I)
Though there are over 70,000 children in Phase I, about half of them were born to parents who were NIC. Another 15,000 children were born to couples who were distally exposed. In other words, over 50,000 children were born to parents, both or either of whom were NIC or distally exposed. In many of the remaining 21 cells, there are less than 50 children. Since the chance of being born as a boy or a girl is 50-50 (almost), there should be fairly large number of children for analysis of sex ratio. With a smaller sample, the confidence interval will be very large.
I re-examined the sex ratio data using three dose groups, viz., NIC, 0 rad and 1+ rad. Considering the exposure of mother and father, there are nine dose groups in the new analysis. In the reanalysis, there was a statistically significant difference between the sex ratio of children born to distally-exposed couples and NIC couples. RERF considered both these as the control group. Even though two control groups make a finding more reliable, differences between the control groups will render all comparisons and analyses meaningless. A suitable control group had to be located. SR of children born to Japanese nationals in Japan during the decade 1948-58 was 1056. The SR of Japanese children born during the second half of the 20th century ranged between 1055-1065. Incidentally, this is the range of sex ratio in all major countries with reliable statistics like India, UK, Canada and USA. When all the Japanese children are considered as the control group, the results of the reanalysis are on the expected lines as follows: (a) excess male among the children of the exposed fathers, (b) excess female among the children of exposed mothers. An unusual finding was an abnormally high sex ratio of 1120 boys per 1000 girls among the parents who were NIC ATB. As mentioned above, the NIC group also included the early entrants, whose exposure has been acknowledged by the Japanese government (vide ABTSML 1958).
Sex Ratio Study (Phase II)
While a real effect on the sex ratio was masked by endless dis-aggregation, the second phase data shows an abnormally high sex ratio of about 1,200 boys per 1,000 girls. The birth sex ratio of Japan has never been over 1060 during the past half a century. In almost all the countries where correct statistics are available, the birth sex ratio ranges between 1040-1065. The unusually high sex ratio during the second phase shows that the data has been doctored.
A comparison of data published in TR 8/71 and the earlier three reports from ABCC/RERF also reveals sex-specific shifting of children between exposure categories, without offering any explanation. JV Neel and WJ Schull, the authors of the genetic study are considered to be authorities on human genetic effects.
Conclusion
The findings of LSS, which probes the effects among the exposed persons, appear to be more or less close to reality, as is revealed from a comparison of other long term studies involving medical radiation. At the same time, the effects on the offspring have been masked. One of the reasons for non-reexamination of the genetic database is the unwillingness of the offspring themselves, who are now matured adults and decision-makers. This is what I could assess from my personal interaction with some of the second-generation citizens of the bombed cities. Whatever the scientific position at RERF or UNSCEAR, the general public in Japan believes that the bombs had damaged their gene. Some of the second-generation adolescents had also experienced problems in dating. The survivors simply do not want to create another Buraku. This is also the case with the ongoing exposure through the food chain. The un-fissioned plutonium and the long-lived fission products simply did not evaporate. They have got into the marine eco-system of a country, which is over-dependent upon water for their food. While such sentiments are to be respected, doctoring the data and misinterpretation has played havoc with the rest of the population. Today, the establishment is arguing for an upward revision of genetic doubling dose of radiation from 100 Rads to 500 Rads.
During the first half of the last century, there were several independent efforts to assess the genetic effects of radiation in humans. Though these studies had smaller sample and sought limited endpoints, they all indicated that 'routine' exposure to ionizing radiation could be deleterious to the permanent genetic material. The official study of the offspring of Hibakushas is the single largest genetic epidemiological study, ever undertaken. Mismanagement of this database has concealed the real effect of radiation. Half a century of efforts to estimate the risk has thus been wasted. The operators of radiation facilities today assert that ionizing radiation is not as genotoxic as suggested by scientists like Herman Mueller and others during the first half of the last century.
Estimation of the Genetic Risk from Radiation
In 1928, Herman Mueller demonstrated that ionizing radiation from a 20 kV X-ray could induce genetic mutation in fruit fly. Since the mid forties, millions of people have been exposed to ionizing radiation from uranium mining, nuclear power stations, bomb testing and medical sources. There have been some epidemiological studies among the offspring of radiologists, radiation workers and down-winders which clearly indicate radiation induced genetic changes. In spite of the advances in genetic technology, our understanding of the epidemiology and distribution of spontaneous and radiation-induced genetic disorders is limited.
Genetic disorders are caused by mutation (chemical change of DNA) or loss of a gene in either or both of the parents. There are an estimated 30,000 genes in humans. These are located on 22 pairs of autosomes and one pair of sex chromosomes. Based on the type and the extent of damage, the anomalies caused can be classified as follows:
(a) Chromosomal anomalies. While a normal human has 46 chromosome, there are exceptions. These are either monosomy or trisomy. In the former, instead of 46, there are only 45 chromosomes, while in the latter there are 47 chromosomes. Examples of trisomy are Down syndrome (trisomy 21) and Turner syndrome (trisomy XXX). Other anomalies are translocation (a piece of a chromosome breaks and gets attached to another), deletion, and formation of rings and fragile sites. All these are gross abnormalities, which can be seen in karyograms.
(b) Point Mutation (PM). In this case, a single gene is either mutated or lost. Examples of anomalies caused due to PM are achondroplasia, Marfan syndrome etc.
(c) Long mutation (LM). LM is a recent entry in the literature. In this, several adjacent genes on a chromosome are either lost or mutated. Loss of large pieces of chromosome (large enough to visible with the old microscopes) was earlier known as chromosomal aberration. With the advance of nano-technology, loss or mutations of smaller pieces of chromosome have become visible. Cri-du-chat (Cry of cat) syndrome is caused due to long mutation (deletion) on chromosome No 14.
Anomalies attributed to both PM and LM were earlier known as single gene disorders. Technically cases of LM should have been included in chromosomal disorders. Since diseases now linked to LM were earlier classified as single gene anomalies, the same categorization continues in the name of Mendelian disorders.
An anomaly, say mental retardation, can be caused by (a) a chromosomal aberration, (b) a point/long mutation in one or both of the parents' genes, (c) an insult to the fetus by a teratogenic agent or virus or (d) due to an infection (like encephalitis) during childhood. Before the microscope, the pattern of inheritance was deduced by observing generations of affected people, exactly the same way as Ernst Mendel did with peas. Normally, mode of inheritance of an anomaly is proven, when the same anomaly has been detected in three successive generations. This is not possible in the case of end-of-the-road anomalies, where reproduction does not happen due to physiological or social reasons. Such diseases have been put in a category called 'anomalies of multifactorial origin'. About three-fourth of the human anomalies in which gene is implicated are still in the multifactorial category, even today. Sporadic cases of mental retardation, cerebral palsy, deafness etc., are examples.
With the advent of electron microscopy, the situation has improved to the extent that in selected diseases, the individual gene involved has been identified. At the same time, the recent advances in gene mapping have only added to the confusion. For instance, different genes have been shown to cause the same anomaly. Achondroplasia, a single disease entity, has now been linked to mutation of four individual genes.
Mendelian anomalies can be classified into three- autosomal dominant (AD), autosomal recessive (AR) and X-linked recessive disorders. X-linked diseases are transmitted to the male progenies only from the mothers, who are carriers and are usually not affected by the disease. Hemophilia and color blindness are examples. In autosomal recessive anomalies, a child is affected only when (s)he receives a mutant gene at the same locus from both the parents (Thalassemia, sickle cell syndrome). Dominant anomalies are transmitted from a single parent (post-axial polydactyly, Marfan syndrome). Generally, recessive anomalies are more severe and life threatening than the dominant ones. The incidence of autosomal recessive anomalies may not increase in the immediate generation after the exposure, but an increase may be visible from the next generation onwards. At the same time, incidence other two anomalies and chromosomal disorders will increase in the offspring of the exposed persons.
There are over 12,000 proven genetic anomalies (of LM and PM type) in the Catalogue of Mendelian Disorders compiled by Victor A McKusick. Some of these anomalies are diagnosable at birth, some become visible in childhood and some manifest at fairly late in life. Individually, almost all these anomalies are very rare.
The national regulatory agencies periodically revise the permissible doses of exposure to radiation workers and general public. These standards, which are legally binding, are based on the recommendations of the United Nation's Scientific Committee on Atomic Radiation (UNSCEAR). In the US, the committee on Biological Effects of Ionizing Radiation (BEIR) of the National Academy of Science is entrusted with this task. Though these two are unrelated agencies, their recommendations are more or less similar. The committees review the latest findings from laboratory and epidemiological studies involving radiation.
For estimating the increase due to exposure to a mutagen, we must know the spontaneous incidence of the anomalies in the unexposed population. The spontaneous load of all genetic anomalies in humans is simply not known. There are more or less reliable statistics on individual anomalies like Down syndrome, achondroplasia, Marfan syndrome in industrialized societies.
In the absence of data on spontaneous incidence of all genetic anomalies, the standard setting agencies use birth incidence of about 50 well known anomalies, observed in different towns and not from any single population. This is not a sound assumption since there are about 30,000 genes packed in a tiny germ cell. Since all such studies have been done in populations (predominantly Caucasians of West European origin living in urban areas) exposed to very high levels of exposure from fission products and X-rays, the observed incidence need not necessarily be the spontaneous incidence. K. Sankaranarayanan, editor of Mutation Research and a prominent member of UNSCEAR/BEIR VII, admits that this is not an ideal solution. The first estimate of the spontaneous incidence was done during the sixties based on the then available data. Between the fifties and the nineties, the birth incidence of the selected Mendelian anomalies almost doubled in those locations. In all human genetic studies such increases over time is attributed to 'false negatives' in earlier studies. Since the authors of the earlier studies cannot defend their findings after two or three decades, usually no debate follows.
The other input for risk estimation should be the observed increase after exposure. The radiation community considers the studies among the Hibakushas as the best radio-epidemiological study. Neil and Schull of RERF reported no statistically significant increase in any endpoint in their genetic study among the offspring of exposed parents. For the radiation-induced risk, the standard setters use laboratory findings in mice, pigs and dogs. The spontaneous (background) incidence of anomalies caused due to mutation in mice and other laboratory animals has remained more or less constant across decades. (The mice lead a monotonous life in a time-less, air-conditioned world, and they don’t get to play on the plutonium-laced Sellafield beach, nor do they drink cows' milk with Strontium90.) However, radio-biologist Selby and others recently discovered that they had earlier overestimated the radiation-induced genetic defects in mice. This was because many of the irradiated, asymptomatic mice who parented anomalous offspring were mosaics to the trait. (They had two cell lines, one normal and the other anomalous and they were visibly non-anomalous.) As such, these anomalous offspring were not cases of radiation-induced fresh mutation.
The genetic doubling dose (DD- the dose of radiation required for doubling the spontaneous incidence) in their 1996 estimate was 100 rads. Last year there were discussions (mainly in the journal Mutation Research) suggesting an upward revision of the genetic DD from the existing 100 to 500 rads (LD50 of acute radiation in human is 400 rads) on the following grounds. (a) Increase in the 'spontaneous' incidence of single gene dominant disorders in the Western populations between the sixties and the nineties. (b) Revision of the estimate of radiation-induced fresh mutation in mice mentioned above. The 2001 report of the UNSCEAR, which deals exclusively with hereditary effects, says that the ionizing radiation is not as genotoxic as was assumed earlier.
Half a century of efforts for estimation of genetic risk have added only confusion. In the case of somatic effects (mainly cancer), the radiation-induced risk has been increasing with each revision of UNSCEAR and BEIR. An analysis of the genetic reports shows that with the passage of time, the genetic materials - the eggs and the sperm- have been becoming more and more radio-resistant.
Even though there are few radio-epidemiological studies that revealed a positive association between exposure and increase in genetic anomalies, the official committees prefer the studies of RERF at Hiroshima-Nagasaki. RERF studies are considered to be of better quality because (a) they are prospective (b) the sample size is fairly large and (c) there are cohorts in different dose groups, (d) longer follow-up and (e) more or less reliable dosimetry. The genetic studies initiated in 1948 (GE-3 study) were among the first researches done among the Hibakushas. According to the latest reports from RERF, there were some excesses of effects among the offspring of the exposed persons, but these were not statistically significant.
It is incorrect to say that the radiation-induced genetic effect has not been demonstrated. The radiation community did observe such effects. The present crisis in standard setting can be attributed to the following:
(a) In Hiroshima and Nagasaki there was a real difference in at least one outcome - i.e., the sex ratio of offspring born to the exposed parents. This effect was masked by (i) endless disaggregration of data and (ii) inclusion of parents exposed to residual radiation from the neutron-activation products and fall-out fission products in the control group. (See synopsis of a review of RERF genetic studies)
(b) Non-publication of data generated during three decades in the high natural radiation region (Chavara-Neendakara villages of Kerala State in India) by the Bhabha Atomic Research Centre. In 1959, WHO had recommended a long term genetic epidemiological study of the people living in these villages with high natural radiation and adjoining villages with a normal background radiation.
(c) Refusal to undertake a prospective pregnancy outcome study among the radiation workers in the nuclear facilities.
(d) Lack of independent monitoring. In the case of cancer, experts like Alice Stewart and John Gofman monitor the periodic reports emanating from RERF and other epidemiological studies. There is no one who is reviewing the genetic studies of RERF.
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