Radiation hormesis: the good, the bad, and the ugly

Three aspects of hormesis with low doses of ionizing radiation are presented: the good, the bad, and the ugly. The good is acceptance by France, Japan, and China of the thousands of studies showing stimulation and/or benefit, with no harm, from low dose irradiation. This includes thousands of people who live in good health with high background radiation. The bad is the nonacceptance of radiation hormesis by the U. S. and most other governments; their linear no threshold (LNT) concept promulgates fear of all radiation and produces laws which have no basis in mammalian physiology. The LNT concept leads to poor health, unreasonable medicine and oppressed industries. The ugly is decades of deception by medical and radiation committees which refuse to consider valid evidence of radiation hormesis in cancer, other diseases, and health. Specific examples are provided for the good, the bad, and the ugly in radiation hormesis.     

Origin of the linearity no threshold (LNT) dose–response concept

This paper identifies the origin of the linearity at low-dose concept [i.e., linear no threshold (LNT)] for ionizing radiation-induced mutation. After the discovery of X-ray-induced mutations, Olson and Lewis (Nature 121(3052):673–674, 1928) proposed that cosmic/terrestrial radiation-induced mutations provide the principal mechanism for the induction of heritable traits, providing the driving force for evolution. For this concept to be general, a LNT dose relationship was assumed, with genetic damage proportional to the energy absorbed. Subsequent studies suggested a linear dose response for ionizing radiation-induced mutations (Hanson and Heys in Am Nat 63(686):201–213, 1929; Oliver in Science 71:44–46, 1930), supporting the evolutionary hypothesis. Based on an evaluation of spontaneous and ionizing radiation-induced mutation with Drosophila, Muller argued that background radiation had a negligible impact on spontaneous mutation, discrediting the ionizing radiation-based evolutionary hypothesis. Nonetheless, an expanded set of mutation dose–response observations provided a basis for collaboration between theoretical physicists (Max Delbruck and Gunter Zimmer) and the radiation geneticist Nicolai Timoféeff-Ressovsky. They developed interrelated physical science-based genetics perspectives including a biophysical model of the gene, a radiation-induced gene mutation target theory and the single-hit hypothesis of radiation-induced mutation, which, when integrated, provided the theoretical mechanism and mathematical basis for the LNT model. The LNT concept became accepted by radiation geneticists and recommended by national/international advisory committees for risk assessment of ionizing radiation-induced mutational damage/cancer from the mid-1950s to the present. The LNT concept was later generalized to chemical carcinogen risk assessment and used by public health and regulatory agencies worldwide.     

Effects of cobalt-60 exposure on health of Taiwan residents suggest new approach needed in radiation protection

The conventional approach for radiation protection is based on the ICRP's linear, no threshold (LNT) model of radiation carcinogenesis, which implies that ionizing radiation is always harmful, no matter how small the dose. But a different approach can be derived from the observed health effects of the serendipitous contamination of 1700 apartments in Taiwan with cobalt-60 (T(1/2) = 5.3 y). This experience indicates that chronic exposure of the whole body to low-dose-rate radiation, even accumulated to a high annual dose, may be beneficial to human health. Approximately 10,000 people occupied these buildings and received an average radiation dose of 0.4 Sv, unknowingly, during a 9-20 year period. They did not suffer a higher incidence of cancer mortality, as the LNT theory would predict. On the contrary, the incidence of cancer deaths in this population was greatly reduced-to about 3 per cent of the incidence of spontaneous cancer death in the general Taiwan public. In addition, the incidence of congenital malformations was also reduced--to about 7 per cent of the incidence in the general public. These observations appear to be compatible with the radiation hormesis model. Information about this Taiwan experience should be communicated to the public worldwide to help allay its fear of radiation and create a positive impression about important radiation applications. Expenditures of many billions of dollars in nuclear reactor operation could be saved and expansion of nuclear electricity generation could be facilitated. In addition, this knowledge would encourage further investigation and implementation of very important applications of total-body, low-dose irradiation to treat and cure many illnesses, including cancer. The findings of this study are such a departure from expectations, based on ICRP criteria, that we believe that they ought to be carefully reviewed by other, independent organizations and that population data not available to the authors be provided, so that a fully qualified epidemiologically-valid analysis can be made. Many of the confounding factors that limit other studies used to date, such as the A-bomb survivors, the Mayak workers and the Chernobyl evacuees, are not present in this population exposure. It should be one of the most important events on which to base radiation protection standards.     

Commentary on Using LNT for Radiation Protection and Risk Assessment

An article by Jerome Puskin attempts to justify the continued use of the linear no-threshold (LNT) assumption in radiation protection and risk assessment. In view of the substantial and increasing amount of data that contradicts this assumption; it is difficult to understand the reason for endorsing this unscientific behavior, which severely constrains nuclear energy projects and the use of CT scans in medicine. Many Japanese studies over the past 25 years have shown that low doses and low dose rates of radiation improve health in living organisms including humans. Recent studies on fruit flies have demonstrated that the original basis for the LNT notion is invalid. The Puskin article omits any mention of important reports from UNSCEAR, the NCRP and the French Academies of Science and Medicine, while citing an assessment of the Canadian breast cancer study that manipulated the data to obscure evidence of reduced breast cancer mortality following a low total dose. This commentary provides dose limits that are based on real human data, for both single and chronic radiation exposures.Jerome Puskin’s perspective on the use of the linear no-threshold (LNT) assumption for radiation protection and risk assessment (Puskin 2009) raises the question: does the U.S. Environmental Protection Agency (EPA) really protect the public or only the established worldwide practice of protecting people from radiation, which costs hundreds of billions of dollars a year? EPA exposure limits are many orders of magnitude below the levels where there is evidence of harm (Jaworowski 1999, Sanders 2010), leading to inappropriate restrictions on the use of nuclear energy to generate electricity and on the use of ionizing radiation in medicine to diagnose serious illnesses. Harmless and beneficial doses should not be regulated. Living organisms can adapt and have adapted to natural radiation, which ranges in intensity from about 0.1 to more than 70 rem per year.The assumptions and models employed by the EPA are not based on modern biological science. The LNT assumption of radiation carcinogenesis, formulated more than 50 years ago, was originally based on experiments that were carried out on fruit flies in the mid-1920s (Muller 1954). At that time, it appeared to be reasonable for estimating cancer risk because this risk was considered to be proportional to mutation rate, which was found to be proportional to radiation dose in high dose ranges. Radiobiologists now know that organisms have defenses against DNA damage and that these can be stimulated by low doses. Although the LNT assumption is still widely accepted, it does not reflect reality, and its continued use is causing great social harm, particularly by constraining wider use of nuclear energy and CT diagnostic scans (Scott et al. 2008).Since the mid-1980s, the Central Research Institute of the Electric Power Industry in Japan has been carrying out remarkable studies on health effects of radiation. Their recent research has demonstrated a threshold at about 1 Gy^† for x-ray-induced DNA mutations in fruit flies and activation of repair by low-dose irradiation, which reduced background mutation (Koana et al. 2004, Koana et al. 2007). Gamma ray irradiation of fruit flies at a dose rate of 22.4 mGy per hour reduced lethal mutation frequency below that in the control flies (Ogura et al. 2009), as shown in Figure 1. The original basis for the LNT assumption has therefore been shown to be invalid.Open in a separate windowFIGURE 1In selecting reports from scientific advisory bodies, the EPA appears to have omitted Scientific Annex B in UNSCEAR 1994, which assessed 192 scientific publications that provide evidence of beneficial health effects of low doses or low dose rates of radiation. The EPA also did not select the report of the French Academy of Science (Académie des sciences 1997), or the joint report of the French Academies of Medicine and Science (Tubiana et al. 2005) both of which raise doubts about the validity of the LNT hypothesis at low doses. A more recent publication in Radiology points out that the LNT relationship is inconsistent with data (Tubiana et al, 2009).Lauriston Taylor, former president of the National Council on Radiation Protection and Measurements (Taylor 2010), denounced the use of a procedure to calculate the expected number of deaths per year resulting from x-ray diagnoses, as follows (Taylor 1980): “These are deeply immoral uses of our scientific heritage.” Unfortunately, this advice was ignored when scientists assessing the Chernobyl accident projected up to 28,000 excess cancer deaths using the LNT assumption and high-dose Hiroshima-Nagasaki data (Catlin et al. 1987). “No one has been identifiably injured by radiation while working within the first numerical standards set by the ICRP in 1934 (safe dose limit: 0.2 rad per day)” (Taylor 1980). Yet members of the U.S. public are limited to 0.5 rem per year.The LNT methodology, as it is generally applied by radiation protection organizations, was tested by a comprehensive study of radon levels in U.S. homes. It failed the test (Cohen 1995).Puskin cites the Howe and McLaughlin 1996 assessment of the Canadian breast cancer study of tuberculosis (TB) patients (Miller et al. 1989) as support for the LNT model, which has been fitted to the Hiroshima-Nagasaki life span study data. However, this assessment manipulated the breast cancer mortality data in a manner that concealed the evidence of protection by low doses that Edward Webster revealed in his Lauriston S. Taylor lecture to the NCRP (Webster 1992). Figure 2 shows the configuration for the fluoroscopy examinations. Figure 3 is Webster’s graph of the Miller et al. data for patients treated for TB between 1930 and 1952. The Nova Scotia patients received a breast dose of 50 mGy (5 rad) per exposure. The patients in the other provinces received a dose of 2 mGy per exposure. Webster fitted straight lines to the high dose data points, and he extended the lines to the breast cancer death rate of the unexposed subjects. The number of exposed subjects in the “other provinces” is 12,094, while the number of unexposed subjects is 17,557. The graph suggests that women who received a total breast dose of 0.15 Gy (15 rad) have a death rate one-third lower than the breast cancer death rate for unexposed women.Open in a separate windowFIGURE 2Open in a separate windowFIGURE 3The Howe-McLaughlin study combined three low-dose data ranges, averaging risk over the wide dose interval 0.01 to 0.49 Gy, and thus obscured the evidence that low doses of radiation provide the benefit of reduced breast cancer mortality. This evidence is highly relevant to the risk of mammography performed repeatedly over a long period of time. This manipulation of low-dose data is one of several “tricks” that epidemiologists have been using over the years to obscure evidence of radiation hormesis (Scott et al. 2008, Scott 2008).A recent review of nuclear energy and health (Cuttler and Pollycove 2009) concludes: “Based upon human data, a single whole body dose of 150 mSv (15 rem) is safe. The high background of 700 mSv/year (70 rem/year) in the city of Ramsar, Iran is also a safe dose limit for continuous chronic exposure. Both dose limits are also beneficial.”     

Commentary on Inhaled 239PUO2 in Dogs — A Prophylaxis Against Lung Cancer?

Several studies on the effect of inhaled plutonium-dioxide particulates and the incidence of lung tumors in dogs reveal beneficial effects when the cumulative alpha-radiation dose is low. There is a threshold at an exposure level of about 100 cGy for excess tumor incidence and reduced lifespan. The observations conform to the expectations of the radiation hormesis dose-response model and contradict the predictions of the LNT hypothesis. These studies suggest investigating the possibility of employing low-dose alpha-radiation, such as from ²³⁹PuO₂ inhalation, as a prophylaxis against lung cancer.     

Shifting the Paradigm in Radiation Safety

The current radiation safety paradigm using the linear no-threshold (LNT) model is based on the premise that even the smallest amount of radiation may cause mutations increasing the risk of cancer. Autopsy studies have shown that the presence of cancer cells is not a decisive factor in the occurrence of clinical cancer. On the other hand, suppression of immune system more than doubles the cancer risk in organ transplant patients, indicating its key role in keeping occult cancers in check. Low dose radiation (LDR) elevates immune response, and so it may reduce rather than increase the risk of cancer. LNT model pays exclusive attention to DNA damage, which is not a decisive factor, and completely ignores immune system response, which is an important factor, and so is not scientifically justifiable. By not recognizing the importance of the immune system in cancer, and not exploring exercise intervention, the current paradigm may have missed an opportunity to reduce cancer deaths among atomic bomb survivors. Increased antioxidants from LDR may reduce aging-related non-cancer diseases since oxidative damage is implicated in these. A paradigm shift is warranted to reduce further casualties, reduce fear of LDR, and enable investigation of potential beneficial applications of LDR.     

Linear No-Threshold Model VS. Radiation Hormesis

The atomic bomb survivor cancer mortality data have been used in the past to justify the use of the linear no-threshold (LNT) model for estimating the carcinogenic effects of low dose radiation. An analysis of the recently updated atomic bomb survivor cancer mortality dose-response data shows that the data no longer support the LNT model but are consistent with a radiation hormesis model when a correction is applied for a likely bias in the baseline cancer mortality rate. If the validity of the phenomenon of radiation hormesis is confirmed in prospective human pilot studies, and is applied to the wider population, it could result in a considerable reduction in cancers. The idea of using radiation hormesis to prevent cancers was proposed more than three decades ago, but was never investigated in humans to determine its validity because of the dominance of the LNT model and the consequent carcinogenic concerns regarding low dose radiation. Since cancer continues to be a major health problem and the age-adjusted cancer mortality rates have declined by only ∼10% in the past 45 years, it may be prudent to investigate radiation hormesis as an alternative approach to reduce cancers. Prompt action is urged.     

Evidence Supporting Radiation Hormesis in Atomic Bomb Survivor Cancer Mortality Data

A recent update on the atomic bomb survivor cancer mortality data has concluded that excess relative risk (ERR) for solid cancers increases linearly with dose and that zero dose is the best estimate for the threshold, apparently validating the present use of the linear no threshold (LNT) model for estimating the cancer risk from low dose radiation. A major flaw in the standard ERR formalism for estimating cancer risk from radiation (and other carcinogens) is that it ignores the potential for a large systematic bias in the measured baseline cancer mortality rate, which can have a major effect on the ERR values. Cancer rates are highly variable from year to year and between adjacent regions and so the likelihood of such a bias is high. Calculations show that a correction for such a bias can lower the ERRs in the atomic bomb survivor data to negative values for intermediate doses. This is consistent with the phenomenon of radiation hormesis, providing a rational explanation for the decreased risk of cancer observed at intermediate doses for which there is no explanation based on the LNT model. The recent atomic bomb survivor data provides additional evidence for radiation hormesis in humans.     

Atomic Bomb Survivors Life-Span Study: Insufficient Statistical Power to Select Radiation Carcinogenesis Model

The atomic bomb survivors life-span study (LSS) is often claimed to support the linear no-threshold hypothesis (LNTH) of radiation carcinogenesis. This paper shows that this claim is baseless. The LSS data are equally or better described by an s-shaped dependence on radiation exposure with a threshold of about 0.3 Sievert (Sv) and saturation level at about 1.5 Sv. A Monte-Carlo simulation of possible LSS outcomes demonstrates that, given the weak statistical power, LSS cannot provide support for LNTH. Even if the LNTH is used at low dose and dose rates, its estimation of excess cancer mortality should be communicated as 2.5% per Sv, i.e., an increase of cancer mortality from about 20% spontaneous mortality to about 22.5% per Sv, which is about half of the usually cited value. The impact of the “neutron discrepancy problem” – the apparent difference between the calculated and measured values of neutron flux in Hiroshima – was studied and found to be marginal. Major revision of the radiation risk assessment paradigm is required.     

Radiation Hormesis: Historical Perspective and Implications for Low-Dose Cancer Risk Assessment

Current guidelines for limiting exposure of humans to ionizing radiation are based on the linear-no-threshold (LNT) hypothesis for radiation carcinogenesis under which cancer risk increases linearly as the radiation dose increases. With the LNT model even a very small dose could cause cancer and the model is used in establishing guidelines for limiting radiation exposure of humans. A slope change at low doses and dose rates is implemented using an empirical dose and dose rate effectiveness factor (DDREF). This imposes usually unacknowledged nonlinearity but not a threshold in the dose-response curve for cancer induction. In contrast, with the hormetic model, low doses of radiation reduce the cancer incidence while it is elevated after high doses. Based on a review of epidemiological and other data for exposure to low radiation doses and dose rates, it was found that the LNT model fails badly. Cancer risk after ordinarily encountered radiation exposure (medical X-rays, natural background radiation, etc.) is much lower than projections based on the LNT model and is often less than the risk for spontaneous cancer (a hormetic response). Understanding the mechanistic basis for hormetic responses will provide new insights about both risks and benefits from low-dose radiation exposure.     

Hypothesis testing and the choice of the dose-response model

The shape of the dose-response curve for exposure to ionising radiation is probably one of the most contentious issues in toxicology. The initial assumption was that there was a threshold to the appearance of a health detriment, including cancer, with the so-called linear-no-threshold (LNT) hypothesis first being introduced in the early 1960s. Since that time a number of models have been suggested, and present work in health physics, toxicology and epidemiology is concerned with questions about both the shape of the dose-response curve and whether or not a threshold exists. This paper presents an analysis of the robustness of the LNT hypothesis from a philosophy of science standpoint-arguing that claims about dose-response curve need to pay more attention to the assumptions and auxillary hypotheses behind choices, and that further mechanistic studies are required to unravel the effects of exposure to ionising radiation. It suggests that whereas LNT falls short of the requirements for a good scientific hypothesis, it is a reasonable model for regulating the carcinogenic and hereditary effects of radiation exposure.     

Perspective on the Use of LNT for Radiation Protection and Risk Assessment By The U.S. Environmental Protection Agency

The U.S. Environmental Protection Agency (EPA) bases its risk assessments, regulatory limits, and nonregulatory guidelines for population exposures to low level ionizing radiation on the linear no-threshold (LNT) hypothesis, which assumes that the risk of cancer due to a low dose exposure is proportional to dose, with no threshold. The use of LNT for radiation protection purposes has been repeatedly endorsed by authoritative scientific advisory bodies, including the National Academy of Sciences’ BEIR Committees, whose recommendations form a primary basis of EPA’s risk assessment methodology. Although recent radiobiological findings indicate novel damage and repair processes at low doses, LNT is supported by data from both epidemiology and radiobiology. Given the current state of the science, the consensus positions of key scientific and governmental bodies, as well as the conservatism and calculational convenience of the LNT assumption, it is unlikely that EPA will modify this approach in the near future.     

The fate of 4-hydroxycarbazole metabolite: metabolism and carcinogenicity assessment of a β-adrenergic receptor modulator containing carbazole structure

1. LY377604 has a potential to form 4-hydroxycarbazole, which was reported in the literature as a mutagen. This safety concern led to our investigation of the metabolism and carcinogenicity of LY377604.

2. In in vitro studies with LY377604, 4-hydroxycarbazole was detected in the presence of liver microsomes prepared from different species. When incubated with liver slices, only the conjugate of 4-hydroxycarbazole was detected.

3. Subsequent in vivo radio-labelled studies were conducted to characterise the formation of 4-hydroxycarbazole from LY377604. Free 4-hydroxycarbazole was not detected in vivo, but the O-glucuronide conjugate was identified as a minor metabolite in urine samples, representing 0.2% and 0.9% of the radioactive dose in rats and monkeys. The low level of circulating 4-hydroxycarbazole glucuronide conjugate was also detected in plasma.

4. LY377604 was negative in all genetic toxicology assays and was not associated with tumour induction in a 6-month carcinogenicity study using RasH2+/? mouse model. The exposure to free 4-hydroxycarbazole was not measurable after one dose and was about 0.1%?0.2% of the parent exposure at the end of the 6-month study.

5. These data suggested that 4-hydroxycarbazole was formed as a minor metabolite in vivo, but it was primarily conjugated and excreted in urine as the glucuronide conjugate. The absence of tumours in the carcinogenicity study combined with the exposure data suggested that the low level of free 4-hydroxycarbazole did not represent a carcinogenic risk.

     

Early effects of acute γ-radiation on vascular arterial tone

1. To determine the acute effects of irradiation on the functionality of vessel, rat aortic rings were mounted in an organ bath for isometric tension measurements and irradiated (⁶⁰Co, 1 Gy min⁻¹, 15 min).
2. Irradiation, which is without effect on non-contracted or endothelium-denuded vessels, led to an immediate and reversible increase in vascular tone on (−)-phenylephrine (1 μM)-precontracted aortic rings. The tension reached a plateau about 5 min after the beginning of irradiation.
3. The maximal radiation-induced contraction occurred on aortic rings relaxed by acetylcholine (ACh) (1 μM). In this condition, the addition of catalase (1000 u ml⁻¹), which reduces hydrogen peroxide, and DMSO (0.1% v/v), which scavenges hydroxyl radical, had no influence on tension level while superoxide dismutase (SOD) (100 u ml⁻¹), a superoxide anion scavenger, reduced the observed contraction. A similar result was obtained in the presence of indomethacin (10 μM), a cyclo-oxygenase blocker.
4. Pretreatment of rings with the nitric oxide synthase inhibitor, N_ω-nitro-L-arginine methyl ester (L-NAME) (10–100 μM) inhibited the radiation-induced contraction.
5. This effect was dose rate-dependent and even occurred for a very low dose rate (0.06 Gy min⁻¹).
6. The present results indicate that γ-radiation induces an instantaneous vascular tone increase that is endothelium and dose rate-dependent. This effect is (i) maximal when nitric oxide (NO) is produced, (ii) greatly reduced by SOD and (iii) inhibited by L-NAME, suggesting a major involvement of complexes between NO and superoxide anion.

     

Application of a novel integrated toxicity testing strategy incorporating “3R” principles of animal research to evaluate the safety of a new agrochemical sulfoxaflor

Abstract

Plant protection products (PPPs) and the active substance(s) contained within them are rigorously and comprehensively tested prior to registration to ensure that human health is not impacted by their use. In recent years, there has been a widespread drive to have more relevant testing strategies (e.g., ILSI/HESI-ACSA and new EU Directives), which also take account of animal welfare, including the 3R (replacement, refinement, and reduction) principles. The toxicity potential of one such new active substance, sulfoxaflor, a sulfoximine insecticide (CAS #946578-00-3), was evaluated utilizing innovative testing strategies comprising: (1) an integrated testing scheme to optimize information obtained from as few animals as possible (i.e., 3R principles) through modifications of standard protocols, such as enhanced palatability study design, to include molecular endpoints, additional neurotoxicity and immunotoxicity parameters in a subchronic toxicity study, and combining multiple test guidelines into one study protocol; (2) generation of toxicokinetic data across dose levels, sexes, study durations, species, strains and life stages, without using satellite animals, which was a first for PPP development, and (3) addition of prospective mode of action (MoA) endpoints within repeat dose toxicity studies as well as proactive inclusion of specific MoA studies as an integral part of the development program. These novel approaches to generate key data early in the safety evaluation program facilitated informed decision-making on the need for additional studies and contributed to a more relevant human health risk assessment. This supplement also contains papers which describe in more detail the approach taken to establish the MoA and human relevance framework related to toxicities elicited by sulfoxaflor in the mammalian toxicology studies:

1. developmental toxicity in rats mediated via the fetal muscle nicotinic acetylcholine receptor (nAChR) ();

2. liver tumors in rodents mediated via CAR/PXR (); and

3. Leydig cell tumors in Fischer 344 rats ()

     

Remedy for Radiation Fear — Discard the Politicized Science

Seeking a remedy for the radiation fear in Japan, the author re-examined an article on radiation hormesis. It describes the background for this fear and evidence in the first UNSCEAR report of a reduction in leukemia of the Hiroshima survivors in the low dose zone. The data are plotted and dose-response models are drawn. While UNSCEAR suggested the extra leukemia incidence is proportional to radiation dose, the data are consistent with a hormetic J-shape and a threshold at about 100 rem (1 Sv). UNSCEAR data on lifespan reduction of mammals exposed continuously to gamma rays indicate a 2 gray/year threshold. This contradicts the conceptual basis for radiation protection and risk determination established in 1956–58. In this paper, beneficial effects and thresholds for harmful effects are discussed, and the biological mechanism is explained. The key point: the rate of DNA damage (double-strand breaks) caused by background radiation is 1000 times less than the endogenous (spontaneous) rate. It is the effect of radiation on an organism’s very powerful adaptive protection systems that determines the dose-response characteristic. Low radiation up-regulates the protection systems, while high radiation impairs these systems. The remedy for radiation fear is to expose and discard the politicized science.

The great tragedy of science—the slaying of a beautiful hypothesis by an ugly fact.—Huxley TH. English biologist (1825–1895)

     

Dose-effect study of domperidone as a galactagogue in preterm mothers with insufficient milk supply, and its transfer into milk

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Domperidone is an effective treatment for some mothers with insufficient milk supply.
• However, dose–effect data are not available, and the safety of domperidone use in both mother and infant has been questioned.

WHAT THIS STUDY ADDS

• Domperidone only increases milk production in about two-thirds of preterm mothers with insufficient milk supply.
• On average, the responders showed increasing levels of milk production with dose escalation from 30 mg to 60 mg daily.
• The amount of domperidone that transferred into breast milk was very low, and the risk to the breastfed infant is minimal.

AIMS

To investigate the possibility of a dose–response relationship for the use of domperidone in treating insufficient milk supply in mothers of preterm infants, and to quantify the exposure of the breastfed infant to domperidone.

METHODS

Six preterm mothers received domperidone (30 mg daily or 60 mg daily) in a double-blind, randomized, crossover trial. Milk production and serum prolactin were measured before and during the trial, and domperidone concentration in milk was measured during drug treatment.

RESULTS

For milk production, two of the mothers were ‘nonresponders’, whereas the other four were ‘responders’ and showed a significant increase in milk production from 8.7 ± 3.1 g h⁻¹ in the run-in phase (mean ± SEM), 23.6 ± 3.9 g h⁻¹ for the 30-mg dose (P = 0.0217) and 29.4 ± 6.6 g h⁻¹ for the 60-mg dose (P = 0.0047). In all participants, serum prolactin was significantly increased for both doses, but the response was not dose dependent. Median (interquartile range) domperidone concentrations in milk over a dose interval at steady-state were 0.28 µg l⁻¹ (0.24–0.43) and 0.49 µg l⁻¹ (0.33–0.72) for the 30-mg and 60-mg doses, respectively. The mean relative infant dose was 0.012% at 30 mg daily and 0.009% at 60 mg daily.

CONCLUSION

In one-third of mothers, domperidone did not increase milk production. In the remainder, milk production increased at both domperidone doses, and there was a trend for a dose–response relationship. The amount of domperidone that transfers into milk was extremely low, and infant exposure via breastfeeding was not considered to be significant.     

Pharmacokinetics of recombinant human soluble thrombomodulin,thrombomodulin alfa in the rat

1. The study aimed to investigate the pharmacokinetics of thrombomodulin alpha (TM-α), human-soluble thrombomodulin in rats.

2. Intravenously administered TM-α was eliminated in two phases (T_1/2α = 0.2–0.3 h and T_1/2β = 6–8 h), and the elimination curve was linear in a dose range of 10–250 μg kg^?1. Based on the results of tissue concentration studies after reaching the steady-state, the highest concentration of TM-α was seen in the plasma, suggesting the low levels of transfer to tissues (≤ 22% of plasma levels).

3. In vivo metabolism of TM-α was also analysed using high-performance liquid chromatography. The main peak observed in the plasma was TM-α, and even 72 h after the last dose of repeated administrations, 80% or more was unchanged form. Approximately half of the radioactivity excreted in the urine was recovered as a peak corresponding to TM-α.

4. The results reveal that although plasma clearance was lower in the renally impaired rats, the decrease was not large, with a difference of only about 20%. As a result, although the cause remains unclear, it is considered unlikely that the plasma concentrations of TM-α will vary considerably in patients with renal impairment.

     

Association between Local External Gamma Rays and Frequency of Cancer in Babol-Iran

Introduction:

The effect of natural background radiation on Cancer is still challenging. The investigation of association between external gamma rays and Cancer was the main goal of study.

Materials & Methods:

External Gamma rays were measured using a radiation survey meter in 184 urban and rural health centers to estimate the exposure to the population in residential areas of Babol. The dose distribution map was compared to the 5 years radiation induced cancer incidence data from cancer registry center in north part of Iran.

Results:

Results showed that although the external gamma ray level in Babol is nearly equal to the average natural background radiation in the world, there is a relatively weak inverse association between local external gamma ray and incidence of Cancer [Correlation coefficient = −0.43, (p<0.01)].

Conclusion:

This finding might be due to the inhibition of cancer induction following exposure to the low doses of ionizing radiation and probably can be a confirmation of radiation hormesis. However, due to some uncertainties, the conclusion should be interpreted with caution. Further national and international studies are suggested.     

Homeless Drug Users in Rotterdam,The Netherlands: Profile,Way of Life,and the Need for Assistance

Decreasing the number of homeless drug users is one of the main characteristics of inner city drugs policy. The present study selected an urban-ethnographic perspective (the subculture theory) in order to explore why one drug user is homeless and another 7 not, and to attempt to describe and define the homeless and their immediate social environment. These issues were formulated into the following research questions:

1. What are the sociodemographic characteristics of homeless drug users in Rotterdam, and do they differ from domiciled drug users?

2. What are their living conditions?

3. What are the reasons for being homeless?

4. Does the period of homelessness play a role in the need to change one's lifestyle?

Five research methods were employed for this study: a literature search, interviews with key persons, field notes from community fieldworkers, a survey among drug users (n = 204), and photographic reports from six homeless users. Data were collected in 1998/1999. The results document that in our study population there were more women, more illegal persons, and more foreigners than among domiciled drug users, and that the homeless group used heroin and cocaine on more days. A large proportion of the homeless users had no identity papers and no health insurance. This did not, however, lead to more self-reported sickness or a higher prevalence of infectious diseases compared with nonhomeless drug users. Easily accessible (low threshold) social care centers and assistance are very important. Few of the homeless had voluntarily chosen a homeless life—most describe an event that was a trigger for their homelessness. The average duration of being homeless was 17 months, and the longer someone had been homeless the less inclined they were to change their situation. This paper also discusses policymaking implications.