Cradle-to-cradle stewardship of drugs for minimizing their environmental disposition while promoting human health. I. Rationale for and Avenues toward a Green Pharmacy - Green Pharmacy Mini-Monograph

Environmental Health Perspectives, May, 2003 by Christian G. Daughton

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Because of the extraordinary complexity of both exposure and outcome, toxicologists usually are forced to look at cause-effect issues "out of context": The historic ramification has been to consider exposure solely as a function of a single toxicant or a very limited set of chemical stressors. The overall picture, however, is complicated not just by the large universe of potential toxicants to which an organism can normally be exposed at any point (or period) of time but also by the host of other variables such as exposure level, exposure route (e.g., dermal, enteral, pulmonary), exposure timing (windows of vulnerability, e.g., developmental stage), prior exposure history, prior exposure duration (e.g., acute--short-term, sequential, intermittent, episodic--or chronic), nutrition, age, sex, genetics, and nonchemical costressors (temperature, physical/metabolic stress, noise, electromagnetic radiation, pathogens). All these factors determine an organism's historic "exposure trajectory," which in turn determines its current health status and sets the stage for the outcome of current exposure (vulnerability vs. resistance to homeostasis perturbation). With science's limited understanding of this complex, dynamic interplay of multiple factors, risk assessment is necessarily restricted to assessing the ramifications of potential adverse toxic events without the larger holistic perspective.

A convenient shorthand term that captures the complete context of an organism's cumulative exposure to chemical stressors does not exist. One possibility offered here is "toxicant-totality-tolerance-trajectory" (the "4Ts"; see Daughton/U.S. EPA 2003a), which accounts for an organism's complete exposure time line (a trajectory described by prior multidimensional exposure history) and the fact that a major objective of all organisms is to maintain homeostasis (in the face of continual perturbation by stressors). Homeostasis can be maintained only within the tolerance bounds for the organism's biochemical defensive repertoire. So the 4Ts describe the hypothetical overall true risk as reflected by the sum total of exposure to all toxicants (anthropogenic and naturally occurring) throughout the historical multidimensional space and trajectory of all other exposure variables. A key aspect to this concept is the critical state determined by the 4Ts--the state at which an additional single exposure event can result in an adverse effect.

The documented occurrence of PPCPs in the environment may or may not eventually have any implications regarding either ecologic or human health--primarily because their known concentrations are so low [nanograms per liter (parts per trillion) to micrograms per liter (parts per billion)]. The issues associated with potential ecologic effects in particular cannot be resolved until aquatic and computational toxicologists (for an overview of computational toxicology, see Bradley 2002) begin to evaluate the effects on nontarget organisms by simultaneous, long-term exposure to multiple PPCPs at low doses and to assess the significance of cumulative exposure to PPCPs sharing the same biochemical mechanism of action (MOA). Indeed, therapeutic doses for target organisms (which are often many orders of magnitude higher than dissolved waste concentrations) may not be relevant benchmarks against which to assess risks to nontarget species. Furthermore, environmental monitoring tends to focus on concentrations of PPCPs dissolved in water (because of their water solubility). This emphasis, however, could underestimate environmental loads by unknown magnitude because of sorption to suspended particulates, sediments, or sewage biosolids; this could prove critically significant regarding interface phenomena and lead to higher than projected exposure levels (e.g., exposure of microorganisms to antibiotics).