Mohan Doss, PhD
Office Phone: 215-214-1707
Fox Chase Programs
Overview of Research Interests
Health Effects of Low Dose Radiation
Whereas the carcinogenic nature of high dose radiation is well known, there is considerable disagreement in the scientific community regarding the health effects of low dose radiation. The traditional assumption and the prevailing view is that the cancer risk can be extrapolated from high dose radiation to low dose radiation linearly with no threshold (LNT model). The LNT model has been used for radiation safety purposes since the 1950s and has led to the perception among the public and the scientists that even the smallest dose of radiation can increase the risk of cancer.
The use of the LNT model implies dismissing the importance of adaptive defensive response to the low dose radiation. However, many animal studies have shown adaptive response of increased antioxidants, increased immune response, etc when subjected to low dose radiation. How important is it to consider the adaptive responses for human health?
Let us consider the case of anti-angiogenesis therapies for cancer. It is well known that tumors cannot grow to more than 1-2 mm in size unless there is blood vessel growth accompanying the tumor to provide the necessary oxygen and nutrition. Tumors are known to release pro-angiogenesis factors, e.g VEGF, that stimulate the growth of blood vessels, enabling them to grow to bigger size. Hence it was surmised that the growth of tumors could be slowed down by administering anti-VEGF agents. This has worked in animal models, and also showed some success in reducing tumor growth in patients. However, the adaptive response of the tumors to the anti-VEGF therapy was to elevate the level of other pro-angiogenesis factors. Hence, when the anti-VEGF treatments were stopped for any reason, the increased pro-angiogenesis factors led to more aggressive tumor growth, increased invasiveness, and increased metastatic disease. Thus, ignoring the impact of adaptive response led to ultimately worsening of the patient health, even though the anti-angiogenesis treatments were well thought out based on sound knowledge of the mechanism of tumor growth.
Another example that illustrates the importance of adaptive response is the occasional cure of untreated distant metastatic lesions following radiation therapy to a primary tumor known as the abscopal effect, which has been observed to be accompanied by an increased anti-tumor immune response. The mechanism of abscopal effect is still being debated. Since high dose radiation suppresses the immune system and low dose radiation enhances it, the increased immune response is most likely from the incidental low dose radiation to parts of body during the radiation therapy. Thus, in this case, incidental adaptive response likely led to cure of metastatic lesions without even targeting.
The contrast between these two observations vividly illustrates the importance of considering adaptive response. The use of the LNT model, as it completely ignores adaptive response, is therefore not justifiable.
The use of the LNT model also implies the nature of biological effect does not change qualitatively between high dose radiation and low dose radiation, except for the scale of the effect. However, in-vitro studies have shown qualitative difference in the genes and proteomes expressed following low doses vs. high doses of radiation, making linear extrapolation of high dose data to low doses of questionable validity. Animal studies have also shown reduced cancers when they were subjected to low dose radiation.
In spite of such evidence, human epidemiological data, in particular atomic bomb survivor cancer mortality data have been used to justify the continued use of the LNT model, for example by the recent BEIR VII report. A corrected analysis of the recent update to atomic bomb survivor data has recently shown that the data cannot exclude the presence of a threshold. In addition, the atomic bomb survivor data have also shown a significant reduction of cancer mortality rate in the 0.3 to 0.7 Gy range in comparison to a linear fit to the data. This feature cannot be explained by the LNT model. However, if a correction is applied to the data for a possible negative bias in the baseline cancer mortality rate, the data becomes consistent with the idea of radiation hormesis, according to which small doses of radiation lead to reduced incidence of cancer. Such a bias could have arisen because of the method of data analysis used in the atomic bomb survivor study.
If the concept of radiation hormesis turns out to be true, it can result in a considerable reduction in cancer mortality. Considering the relative lack of progress reducing in age-adjusted cancer mortality rates in the past fifty years (~10% reduction), it may be prudent to determine the validity of radiation hormesis. The present radiation safety regulations are a major hindrance to any such study, and so should be revised, taking into consideration the importance of adaptive response.Top
Another potential benefit of low dose radiation is the control of aging-related non-cancer diseases through stimulation of production of antioxidants. Since many of these non-cancer diseases are caused by oxidative damage, it may be possible to stabilize the diseases if further oxidative damage can be prevented. If low dose radiation is shown to be effective in control of these diseases in animal studies, such studies may be more acceptable for human trials (in comparison to cancer prevention studies) as they require low dose radiation exposure only to patients identified to have high probability of developing the disease from screening programs. There is evidence in the current literature for reduction of many aging-related diseases in pre-clinical models when subjected to low dose radiation.
Current research projects
Application of Low Dose Radiation Adaptive Response to Control Parkinson’s disease in a rat model:
Our hypothesis is that low dose radiation elevates the level of antioxidants in substantia nigra in rat brain and reduces Parkinson’s disease symptoms in the 6-OHDA-lesion model of the disease. This study is in collaboration with a team at Temple University Hospital Neurology Department led by Barbara Krynska, Ph.D. Experiments are in progress for this study.Top