Relevance of thresholds in determining plausibility. Continuing with the PM example, it is believed that particles exert their primary toxic effects by increasing production of reactive oxygen (ROS) and nitrogen species (RNS). ROS and RNS tend to react chemically, causing damage by “attacking” cell structures and genetic material (e.g., DNA). While very high levels can lead to DNA damage, there is little evidence to suggest that PM can damage DNA in the absence of inflammation, which is a threshold phenomenon due to the many feedback and control processes involved. EPA ISA, supra. The mutagenicity of some hydrocarbon components of ambient PM has been established for decades, but the ability of PM-associated organics to cause DNA damage depends on their release from the particles (i.e., the particles themselves do not cause the mutation). Roel P. Schins & Ad M. Knaapen, “Genotoxicity of Poorly Soluble Particles,” 19 Inhalation Toxicology 189 (2007). Therefore, even though PM may be capable of causing mutation at high levels, the available information does not support that there is no threshold for this effect. The concept that there is a threshold for PM-induced toxicity is supported by mechanism-of-action studies for PM conducted in living animals and human experiments. EPA ISA, supra. Thus, allegations that any increase in PM (no matter how small) will cause harm are not well supported by the science.
Plausibility of cumulative toxicological effects. Another issue in lawsuits alleging harm or injury is the potential impact of cumulative exposure, defined as simultaneous exposure to multiple chemicals at once. The basis for such claims is that chemicals in the mixture may interact in such a way that the doses are additive and the mixture is more potent than any one of the individual chemicals by themselves.
Unfortunately, the scientific literature on chemical interactions is extremely limited. However, one cannot simply assume that the health effects caused by simultaneous exposure to two chemicals that cause the same toxic effect can be accurately predicted by simply summing the doses of the components. Understanding the mechanisms by which the individual chemicals cause the toxic effect is critical to determining whether the response will be additive because strict dose additivity is generally only considered to occur when chemicals exert their toxic effects by the same mechanism of action. ATSDR, Guidance Manual for the Assessment of Joint Toxic Action of Chemical Mixtures (2004); EPA, EPA/600/8-90/064, Technical Support Document on Health Risk Assessment of Chemical Mixtures (1990).
Consider a case in which the plaintiffs claimed cumulative exposure to several compounds potentially emitted from a refinery. Among the chemicals potentially emitted were acrolein, a potential byproduct released when something is burned, and sulfur dioxide (SO2). Both compounds have the potential to cause sensory irritation (i.e., burning, stinging, tingling of eyes and upper airways). Sensory irritation is a receptor-mediated process, which means that receptor proteins bind stimulating agents, causing the body to react in a particular way. Airborne chemicals activate the system mainly at mucous membranes (inside nose, eyes, etc.), where there is easy access to the nerves. The mechanism by which SO2 causes irritation is by splitting the disulfide bond (indicated as S-S in the receptor figure below) on the receptor protein. Other compounds, like acrolein, chemically interact with (i.e., bind) thiol groups (indicated as S-H in the receptor figure below) at the receptor. Gunnar Damgård Nielsen, “Mechanisms of Activation of the Sensory Irritant Receptor by Airborne Chemicals,” 21 Critical Revs. in Toxicology 183 (1991).
Figure 3
As shown in the top panel of the figure below, when mice are exposed to SO2 alone, there is a rapid drop in respiration (experimental indicator of irritation) five minutes after exposure begins, but respiration rebounds to approximately normal within eight minutes, even though exposure to SO2 continued for 15 minutes. The second panel illustrates a different response pattern for acrolein in that, although a decrease in respiration occurred at five minutes, it was slower (i.e., less steep) and the respiration rate did not rebound. (Laurel E. Kane & Yves Alarie, “Interactions of Sulfur Dioxide and Acrolein as Sensory Irritants,” 48 Toxicology & Applied Pharmacology 305 (1979).
The next two panels show response patterns following simultaneous exposure of mice to SO2 and acrolein at high (40:1 ratio) and low (10:1 ratio) SO2 concentrations. When the ratio of SO2 to acrolein is higher, the rapid drop in respiration followed by rebound at eight minutes that are characteristic of SO2 occur, but then the respiration drops again and plateaus, which is characteristic of the acrolein response. When the ratio of SO2 to acrolein is lower, the response looks almost identical to the acrolein response, except that the drop in respiration at five minutes is faster (i.e., steeper).
Figure 4
Source: Kane & Alarie, supra.
These figures show that although the response shows characteristic patterns of each of the individual chemicals when mice are exposed to SO2 and acrolein simultaneously, the response is not additive (i.e., the two are not more potent together). As shown above, the lowest respiration rate is 125 per minute, regardless of whether mice are exposed to SO2 alone, acrolein alone, or SO2 and acrolein simultaneously. Thus, when allegations of cumulative toxicity are made, a toxicologist can help determine whether the mechanisms of action of the chemicals allegedly involved support that simultaneous exposure could potentially be more harmful.