Bobby R. Scott

Polonium-210 as a poison

The death of Alexander Litvinenko on 23 November 2006 has brought into focus scientific judgements concerning the radiotoxicity of polonium-210 ((210)Po). This paper does not consider the specific radiological circumstances surrounding the tragic death of Mr Litvinenko; rather, it provides an evaluation of published human and animal data and models developed for the estimation of alpha radiation doses from (210)Po and the induction of potentially fatal damage to different organs and tissues. Although uncertainties have not been addressed comprehensively, the reliability of key assumptions is considered. Concentrating on the possibility of intake by ingestion, the use of biokinetic and dosimetric models to estimate organ and tissue doses from (210)Po is examined and model predictions of the time-course of dose delivery are illustrated. Estimates are made of doses required to cause fatal damage, taking account of the possible effects of dose protraction and the relative biological effectiveness (RBE) of alpha particles compared to gamma and x-rays. Comparison of LD(50) values (dose to cause death for 50% of people) for different tissues with the possible accumulation of dose to these tissues suggests that bone marrow failure is likely to be an important component of multiple contributory causes of death occurring within a few weeks of an intake by ingestion. Animal data on the effects of (210)Po provide good confirmatory evidence of intakes and doses required to cause death within about 3 weeks. The conclusion is reached that 0.1-0.3 GBq or more absorbed to blood of an adult male is likely to be fatal within 1 month. This corresponds to ingestion of 1-3 GBq or more, assuming 10% absorption to blood. Well-characterised reductions in white cell counts would be observed. Bone marrow failure is likely to be compounded by damage caused by higher doses to other organs, including kidneys and liver. Even if the bone marrow could be rescued, damage to other organs can be expected to prove fatal.

IT'S TIME FOR A NEW LOW-DOSE-RADIATION RISK ASSESSMENT PARADIGM-ONE THAT ACKNOWLEDGES HORMESIS

The current system of radiation protection for humans is based on the linear-no-threshold (LNT) risk-assessment paradigm. Perceived harm to irradiated nuclear workers and the public is mainly reflected through calculated hypothetical increased cancers. The LNT-based system of protection employs easy-to-implement measures of radiation exposure. Such measures include the equivalent dose (a biological-damage-potential-weighted measure) and the effective dose (equivalent dose multiplied by a tissue-specific relative sensitivity factor for stochastic effects). These weighted doses have special units such as the sievert (Sv) and millisievert (mSv, one thousandth of a sievert). Radiation-induced harm is controlled via enforcing exposure limits expressed as effective dose. Expected cancer cases can be easily computed based on the summed effective dose (person-sievert) for an irradiated group or population. Yet the current system of radiation protection needs revision because radiation-induced natural protection (hormesis) has been neglected. A novel, nonlinear, hormetic relative risk model for radiation-induced cancers is discussed in the context of establishing new radiation exposure limits for nuclear workers and the public.

SPARSELY IONIZING DIAGNOSTIC AND NATURAL BACKGROUND RADIATIONS ARE LIKELY PREVENTING CANCER AND OTHER GENOMIC-INSTABILITY-ASSOCIATED DISEASES

Routine diagnostic X-rays (e.g., chest X-rays, mammograms, computed tomography scans) and routine diagnostic nuclear medicine procedures using sparsely ionizing radiation forms (e.g., beta and gamma radiations) stimulate the removal of precancerous neoplastically transformed and other genomically unstable cells from the body (medical radiation hormesis). The indicated radiation hormesis arises because radiation doses above an individual-specific stochastic threshold activate a system of cooperative protective processes that include high-fidelity DNA repair/apoptosis (presumed p53 related), an auxiliary apoptosis process (PAM process) that is presumed p53-independent, and stimulated immunity. These forms of induced protection are called adapted protection because they are associated with the radiation adaptive response. Diagnostic X-ray sources, other sources of sparsely ionizing radiation used in nuclear medicine diagnostic procedures, as well as radioisotope-labeled immunoglobulins could be used in conjunction with apoptosis-sensitizing agents (e.g., the natural phenolic compound resveratrol) in curing existing cancer via low-dose fractionated or low-dose, low-dose-rate therapy (therapeutic radiation hormesis). Evidence is provided to support the existence of both therapeutic (curing existing cancer) and medical (cancer prevention) radiation hormesis. Evidence is also provided demonstrating that exposure to environmental sparsely ionizing radiations, such as gamma rays, protect from cancer occurrence and the occurrence of other diseases via inducing adapted protection (environmental radiation hormesis).

Low-dose radiation risk extrapolation fallacy associated with the linear-no-threshold model.

Managing radiation risks typically involves establishing regulations that limit radiation exposure. The linear-no-threshold (LNT) dose—response model has been the traditional regulatory default assumption. According to the LNT model, for low a linear-energy-transfer (LET) radiation-induced stochastic effects (e.g., neoplastic transformation and cancer), the risk increases linearly without a threshold. Any radiation exposure is predicted to increase the number of cancer cases among a large population of people. Cancer risk extrapolation from high to low doses based on this model is widespread. Here, indirect evidence is provided that the excess cancer risk calculated at very low doses of low-LET radiation (e.g., around 1 mGy), based on extrapolating from high dose data for an irradiated human population using the LNT model, is likely a phantom excess risk. Indirect evidence is provided, suggesting that for brief exposures to low-LET radiation doses on the order of 1 mGy, that a decrease below the spontaneous level is many orders of magnitude more probable than for any increase in risk as would be predicted by extrapolating from high to low doses using the LNT model. Such a decrease is, however, not expected after exposure to high-LET alpha radiation. The risk reduction has been largely attributed to the induction of a protective apoptosis-mediated (PAM) process that selectively eliminates cells that contain genomic instability (e.g., mutant and neoplastically transformed cells). The PAM process appears to require a dose-rate-dependent stochastic threshold for activation whose minimum is estimated to possibly be as low as 0.01 mGy for X-rays and gamma rays. However, if the dose is too high (e.g., above 250mGy for brief exposure at a high rate to X-rays or gamma rays), the PAM process is not expected to be activated. For protracted exposure to X-rays or gamma rays, doses as high as 400 mGy (and possibly higher) may activate the PAM process.

Radiation-stimulated epigenetic reprogramming of adaptive-response genes in the lung: an evolutionary gift for mounting adaptive protection against lung cancer.

Humans are continuously exposed to low-level ionizing radiation from natural sources. However, harsher radiation environments persisted during our planets early years and mammals survived via an evolutionary gift - a system of radiation-induced natural protective measures (adaptive protection). This system includes antioxidants, DNA repair, apoptosis of severely damaged cells, epigenetically regulated apoptosis ( epiapoptosis ) pathways that selectively remove precancerous and other aberrant cells, and immunity against cancer. We propose a novel model in which the protective system is regulated at least in part via radiation-stress-stimulated epigenetic reprogramming (epireprogramming) of adaptive-response genes. High-dose radiation can promote epigenetically silencing of adaptive-response genes ( episilencing ), for example via promoter-associated DNA and/or histone methylation and/or histone deacetylation. Evidence is provided for low linear-energy-transfer (LET) radiation-activated natural protection (ANP) against high-LET alpha-radiation-induced lung cancer in plutonium-239 exposed rats and radon-progeny-exposed humans. Using a revised hormetic relative risk model for cancer induction that accounts for both epigenetic activation ( epiactivation ) and episilencing of genes, we demonstrate that, on average, >80% of alpha-radiation-induced rat lung cancers were prevented by chronic, low-rate gamma-ray ANP. Interestingly, lifetime exposure to residential radon at the Environmental Protection Agencys action level of 4 pCi L−1 appears to be associated with on average a > 60% reduction in lung cancer cases, rather than an increase. We have used underlined italics to indicate newly introduced terminology.

Smoking and Hormesis as Confounding Factors in Radiation Pulmonary Carcinogenesis

Confounding factors in radiation pulmonary carcinogenesis are passive and active cigarette smoke exposures and radiation hormesis. Significantly increased lung cancer risk from ionizing radiation at lung doses < 1 Gy is not observed in never smokers exposed to ionizing radiations. Residential radon is not a cause of lung cancer in never smokers and may protect against lung cancer in smokers. The risk of lung cancer found in many epidemiological studies was less than the expected risk (hormetic effect) for nuclear weapons and power plant workers, shipyard workers, fluoroscopy patients, and inhabitants of high-dose background radiation. The protective effect was noted for low- and mixed high- and low-linear energy transfer (LET) radiations in both genders. Many studies showed a protection factor (PROFAC) > 0.40 (40% avoided) against the occurrence of lung cancer. The ubiquitous nature of the radiation hormesis response in cellular, animal, and epidemiological studies negates the healthy worker effect as an explanation for radiation hormesis. Low-dose radiation may stimulate DNA repair/apoptosis and immunity to suppress and eliminate cigarette-smoke-induced transformed cells in the lung, reducing lung cancer occurrence in smokers.

Mechanistic Basis for Nonlinear Dose-Response Relationships for Low-Dose Radiation-Induced Stochastic Effects

The linear nonthreshold (LNT) model plays a central role in low-dose radiation risk assessment for humans. With the LNT model, any radiation exposure is assumed to increase ones risk of cancer. Based on the LNT model, others have predicted tens of thousands of deaths related to environmental exposure to radioactive material from nuclear accidents (e.g., Chernobyl) and fallout from nuclear weapons testing. Here, we introduce a mechanism-based model for low-dose, radiation-induced, stochastic effects (genomic instability, apoptosis, mutations, neoplastic transformation) that leads to a LNT relationship between the risk for neoplastic transformation and dose only in special cases. It is shown that nonlinear dose-response relationships for risk of stochastic effects (problematic nonlethal mutations, neoplastic transformation) should be expected based on known biological mechanisms. Further, for low-dose, low-dose rate, low-LET radiation, large thresholds may exist for cancer induction. We summarize previously published data demonstrating large thresholds for cancer induction. We also provide evidence for low-dose-radiation-induced, protection (assumed via apoptosis) from neoplastic transformation. We speculate based on work of others (Chung 2002) that such protection may also be induced to operate on existing cancer cells and may be amplified by apoptosis-inducing agents such as dietary isothiocyanates.

EVIDENCE FOR RADIATION HORMESIS AFTER IN VITRO EXPOSURE OF HUMAN LYMPHOCYTES TO LOW DOSES OF IONIZING RADIATION

Previous research has demonstrated that adding a very small gamma-ray dose to a small alpha radiation dose can completely suppress lung cancer induction by alpha radiation (a gamma-ray hormetic effect). Here we investigated the possibility of gamma-ray hormesis during low-dose neutron irradiation, since a small contribution to the total radiation dose from neutrons involves gamma rays. Using binucleated cells with micronuclei (micronucleated cells) among in vitro monoenergetic-neutron-irradiated human lymphocytes as a measure of residual damage, we investigated the influence of the small gamma-ray contribution to the dose on suppressing residual damage. We used residual damage data from previous experiments that involved neutrons with five different energies (0.22–, 0.44–, 1.5–, 5.9–, and 13.7-million electron volts [MeV]). Corresponding gamma-ray contributions to the dose were approximately 1%, 1%, 2%, 6%, and 6%, respectively. Total absorbed radiation doses were 0, 10, 50, and 100 mGy for each neutron source. We demonstrate for the first time a protective effect (reduced residual damage) of the small gamma-ray contribution to the neutron dose. Using similar data for exposure to gamma rays only, we also demonstrate a protective effect of 10 mGy (but not 50 or 100 mGy) related to reducing the frequency of micronucleated cells to below the spontaneous level.

Stochastic thresholds: a novel explanation of nonlinear dose-response relationships for stochastic radiobiological effects.

New research data for low-dose, low- linear energy transfer (LET) radiation-induced, stochastic effects (mutations and neoplastic transformations) are modeled using the recently published NEOTRANS3 model. The model incorporates a protective, stochastic threshold (StoThresh) at low doses for activating cooperative protective processes considered to include presumptive p53-dependent, high-fidelity repair of nuclear DNA damage in competition with presumptive p53-dependent apoptosis and a novel presumptive p53-independent protective apoptosis mediated (PAM) process which selectively removes genomically compromised cells (mutants, neoplastic transformants, micronucleated cells, etc.). The protective StoThresh are considered to fall in a relatively narrow low-dose zone (Transition Zone A). Below Transition Zone A is the ultra-low-dose region where it is assumed that only low-fidelity DNA repair is activated along with presumably apoptosis. For this zone there is evidence for an increase in mutations with increases in dose. Just above Transition Zone A, a Zone of Maximal Protection (suppression of stochastic effects) arises and is attributed to maximal cooperation of high-fidelity, DNA repair/apoptosis and the PAM process. The width of the Zone of Maximal Protection depends on low-LET radiation dose rate and appears to depend on photon radiation energy. Just above the Zone of Maximal Protection is Transition Zone B, where deleterious StoThresh for preventing the PAM process fall. Just above Transition Zone B is a zone of moderate doses where complete inhibition of the PAM process appears to occur. However, for both Transition Zone B and the zone of complete inhibition of the PAM process, high-fidelity DNA repair/apoptosis are presumed to still operate. The indicated protective and deleterious StoThresh lead to nonlinear, hormetic-type dose-response relationships for low-LET radiation-induced mutations, neoplastic transformation and, presumably, also for cancer.

Low-Dose Radiation-Induced Protective Process and Implications for Risk Assessment, Cancer Prevention, and Cancer Therapy

A low-dose protective apoptosis-mediated (PAM) process is discussed that appears to be turned on by low-dose gamma and X rays but not by low-dose alpha radiation. PAM is a bystander effect that involves cross-talk between genomically compromised [e.g., mutants, neoplastically transformed, micronucleated] cells and nongenomically compromised cells. A novel neoplastic cell transformation model, NEOTRANS3, is discussed that includes PAM. With NEOTRANS3, PAM is activated by low doses and inhibited by moderate or high doses and is, therefore, a hormetic process. A low-dose region of suppression of the transformation frequency below the spontaneous frequency relates to the hormetic zone over which PAM is presumed to operate. The magnitude of suppression relates to what is called the hormetic intensity. Both the hormetic intensity and width of the hormetic zone are expected to depend on dose rate, being more pronounced after low dose rates. It is expected that PAM likely had a significant role in the following observations after chronic irradiation: (1) what appears to be a tremendous reduction in the cancer incidence below the spontaneous level for Taiwanese citizens residing for years in cobalt-60 contaminated apartments; and (2) the published reductions in the lung cancer incidence below the spontaneous level in humans after protracted X irradiation and after chronic gamma plus alpha irradiation. Implications of PAM for cancer prevention and low-dose cancer therapy are briefly discussed.