Finlay Smith, Dr Rhona Anderson, Professor Andreas Kortenkamp Centre for Health Effects of Radiological and Chemical Agents (CHRC)

What are we looking at?
The purpose of my research is to investigate whether combined exposures to ionising radiation and genotoxic chemicals (any toxic chemical that acts by damaging DNA) is potentially more hazardous than exposure to either of these agents alone and whether the effects of combined exposures could be predicted correctly for risk assessment purposes.

This is an important question, as the current regulatory system treats chemical hazards and radiation hazards almost entirely separately, and the resulting exposure limits reflect this. If there was a significant risk increase due to combined exposures, these regulatory limits, therefore, have the potential to underestimate the true risk. 

This approach builds on the concept of Mixture Toxicology that is increasingly used to assess pollution impact in the chemical sciences (Kortenkamp, A. and Faust, M., 2018). Mixture toxicology investigates the health effects of exposure to chemical mixtures, both at the human and environmental levels.

The hypothetical example presented below shows a mixture of chemicals (Chemical 1, Chemical 2 and Chemical 3) with a combined effect that is greater than the effect of its most toxic component (Chemical 2).

CHRC Graph 1

We do not know if a similar relationship exists for combined exposures between a chemical mixture and ionising radiation, and this is what I will be investigating in my research.

Mixture Toxicology
Mixture toxicology deals with the concept that chemicals with similar chemical structures or similar biological effects can have a combined mixture effect that has a greater effect than it’s component’s individual toxic effect. Therefore mixtures of several chemicals can present a risk even if each individual component is below levels where routine risk assessments would place the risk as negligible or ‘safe’. 

Mixture toxicity depends on exact mixture composition, whether toxicity is additive or independent in function, which are different conceptual models. And it can also depend on whether or not one component can increase or decrease the activity of another, referred to as synergism or antagonism respectively. 

When the toxicity of individual mixture components is known, mixture effects can be predicted mathematically.

What is the relevance to Nuclear Test Veterans?
While traditionally hazards have been considered separately in any real-world exposure scenario an individual will be exposed to multiple agents present in the environment around us. This is especially true in industrial settings or the military where the use of hazardous chemicals is more frequent. We know from historical accounts and eyewitness testimony that personnel were exposed to high levels of the insecticide DDT, as well as fuel oils and industrial chemicals used in vehicle maintenance, many of which are carcinogenic (can cause cancer) or can contribute to the toxic load on the body. 

A large study that combined data from a number of epidemiological studies (a study of disease incidence correlated with other factors) on European populations (Darby et al, 2005) showed that there is a substantial increase in the absolute risk of lung cancer in smokers in areas where there is higher natural background radiation. In particular, there is an increased risk in homes which have a higher concentration of Radon gas in the air. 

Naturally occurring Radon gas is an alpha-particle emitter which presents a small radiation risk when inhaled. 

The authors of the study reported the absolute risk levels for lung cancer for smokers to be higher than non-smokers at all dose levels, with both increasing proportionally with exposed dose. This is because the existing risk of lung cancer is much higher in smokers due to the mix of carcinogens present in cigarettes. This higher ‘base rate’ means that the same proportional increase in risk per 100 Bq/m3 (a measure of the number of radioactive atoms releasing an alpha-particle per second in one cubic meter of household air) results in a much larger absolute risk in smokers for the same radiation exposure. 

In smokers, cumulative (over a life-time) absolute risk of lung cancer by age 75 was found to be 11.6% with a background radiation level of 100 Bq/m3, and 21.6% with a background radiation level of 800 Bq/m3. In non-smokers this was 0.47% and 0.93% respectively.

This information is presented graphically below.

CHRC Table 2

This shows that exposure to a mixture of carcinogens (cigarette smoke in this instance) in the lung can considerably raise an individual’s risk of developing lung cancer that is correlated with increased radiation exposure to atmospheric Radon alpha particles. 

What does the work entail?
We are conducting a detailed review of all published experimental literature in this area, but this interaction has not been studied in much depth, and what work has been done mostly concerns single chemicals in combination with radiation exposure rather than more realistic multiple exposures. My research, therefore, aims to provide a good experimental basis to examine the effects of radiation exposure in combination with mixtures of genotoxic chemicals in an in vitro system (an experimental setup that does not use a living creature, but cells grown in a culture dish). 

The experimental work will be carried out in Professor Kortenkamp’s laboratory, Brunel University London, and in collaboration with an external collaborator for cell culture irradiation. Cells will be cultured (grown) in small sterile dishes, and exposed to carefully prepared mixtures of genotoxic chemicals and then exposed to alpha particle irradiation to give the cells a radiation dose proportional to the mixture concentration. This is called a fixed mixture ratio approach, and allows for calculation of the combined mixture effects.

The first set of experiments will be conducted using a standard model cell line (identical cells grown from a single sample cell) used in chemical toxicology, which is non-human. Later experiments are planned to conduct the mixed exposure experiment using a human cell line as a model.

As with all experimental work, care must be taken when extrapolating conclusions from a cell line model to the whole organism, however this approach is used routinely in toxicology to assess the potential hazards of exposure, and this work represents an important step in building our knowledge of the risks presented by radiation exposures to individuals in real-world exposure scenarios. 

References
1. Kortenkamp, A. and Faust, M. (2018) Regulate to reduce chemical mixture risk, Science, Vol. 361, Issue 6399, pp. 224-226.

2. Darby, S. et al (2005) Radon in homes and risk of lung cancer: collaborative analysis of individual data from 13 European case-control studies, BMJ Vol. 330, Issue 7485, pp. 223-225.

3.  Peto, R. et al. (1992) Mortality from tobacco in developed countries: indirect estimation from national vital statistics. Lancet Vol. 339: pp. 1268-78.