Law360, NEW YORK (December 04, 2008) -- A recent column ("Precaution In Applying The Precautionary Principle") expressed concerns about the so-called precautionary principle, but unfortunately cited to one of the more extreme views of this policy strategy (claiming, basically, that the principle amounted to guilty until proven innocent). In the U.S., the precautionary principle has been much more narrowly defined.
Fundamentally, it looks at testing done with rats, mice, and like animals, and then decides (based on the results) if caution is warranted and if so, to what extent.
Taking this more reasonable and narrower view of the precautionary principle and applying it to the example of overreaching which the authors have selected (phthalates) leads to a different conclusion; a review of the animal bioassay evidence indicates that caution is warranted in terms of the three phthalates that were permanently banned from children's toys, but suggests that the temporary ban on one of the other three phthalates may not be justified.
The use of animal bioassays is a prudent foundation upon which to build a precautionary principle.
The relevance of experimental animal bioassays to the risk of cancer in humans, for example, rests on four well-accepted observations [a point pounded home, I recall, in my very first toxicology class in graduate school]:
"(a) Experimental animals and humans are mammals sharing many basic genetic, pharmacologic, toxicologic, and carcinogenic responses;
"(b) findings from independently conducted bioassays on the same chemicals are consistent [at least most of the time, unless the experimenters were sloppy];
"(c) all known human carcinogens that have been tested adequately are also carcinogenic in animals and, almost without exception, share identical target sites [the organs may not be identical, but the types of fundamental structural tissue may be]; and,
"(d) nearly one-third of human carcinogens were first discovered to induce cancer through experiments in animals (e.g., 1,3-butadiene, diethylstilbestrol, dioxins, ethylene oxide, 2-naphthylamine, formaldehyde, and vinyl chloride), although most of these were not regulated until human cancer evidence was identified." Huff et al, The Limits of Two-Year Bioassay Exposure Regimens for Identifying Chemical Carcinogens (2008).
Thus, the precautionary principle as applied has depended not upon a guilty-until-proven-innocent paradigm, as the authors of the column have implied, but on giving credence to animal bioassays in ascertaining what risk MAY exist to humans from exposure to the tested chemicals and substances.
Unfortunately, as described in a recent blog entry of mine, even this approach may not be quite good enough to evaluate the full spectrum of possible consequences from exposures to various chemicals and substances.
In http://www.ehponline.org/members/2008/10716/10716.html, researchers took a detailed look at the animal testing done on aspartame, cadmium, and toluene, and also examined the standard testing protocol carried out in carcinogenesis studies.
They noted: "Experimental studies should be designed with optimum sensitivity to identify likely adverse health problems throughout humans'' increasing life span. Humans, of course, consume or are exposed to countless natural and synthetic substances during gestation, nursing, and the rest of their lives.
"In modern societies, proportionally more people are living until their 70s, 80s, and 90s, long after prenatal and childhood exposures and retirement from workplace exposures.
"Because most long-term rodent carcinogenesis studies do not involve in utero exposure and are intentionally terminated after 2 years (104 weeks) of exposure, they cannot shed light on the effects of chemicals on embryos/fetuses/neonates or ''elderly'' animals.
"Likewise, studies truncated after 2 years of exposure do not allow sufficient latency periods for late-developing tumors, such as the 80% of all human cancers that occur after 60 years of age. Because a 2-year-old rat is roughly equivalent to a 60- to 65-year-old person, conventional 2-year-long bioassays cannot detect tumors that will develop later in life." Huff, supra.
Thus, the researchers recommend that "The evidence presented here indicates that extending animal bioassays beyond 2 years and beginning exposure in utero, especially for endocrine-disrupting chemicals [such as phthalates are alleged to do] that ''act'' preferentially in early life ... would provide more reliable and appropriate indicators of human risk." Ibid.
They also note that "To maximize the knowledge gained from costly full-lifetime studies, protocols should be expanded to provide for periodic sacrificing to determine time-to-tumor and biological sampling to determine internal doses, metabolite levels, genetic alterations, and other data relevant to characterizing the pharmacokinetic and pharmacodynamic activity of toxicity and noncancer disease." Ibid. These recommendations clearly have substantial merit.
What might be discovered with such an extended testing regime? An example is shown by a recently published study done on parathion (as a representative of organophosphate pesticides). In http://www.ehponline.org/members/2008/11673/11673.html, rats received daily injections of the compound during their first 4 days of life, a developmental period that corresponds to the second to early third trimester in human gestation.
Doses of 0.1 and 0.2 mg/kg/day were chosen because (a) these concentrations straddle the threshold for barely detectable cholinesterase inhibition, and (b) based on the current literature, they represent the concentrations at which the first signs of reduced weight gain or impaired viability occur. Both doses altered the rats'' metabolism into adulthood, but the effects differed in males and females.
Male rats given the lower dose ate about as much as control rats, but outweighed them throughout the 22-week study. Equally important, they showed signs of pre-diabetes, with elevated fasting serum glucose levels and impaired fat metabolism. High-dose males weighed about as much as controls while consuming less food.
In contrast, both high- and low-dose females weighed less than controls although they consumed at least as much food, indicating a "wasting" condition. This was confirmed by a demonstrated disruption of both glucose and lipid metabolism at both doses. After reaching adulthood, half the rats were switched to a high-fat diet.
Increased fat intake exaggerated parathion’s metabolic effects, particularly in females. The extended methodology thus brought forth an association not seen before, an association between parathion, on the one hand, and obesity and Type 2 diabetes on the other vis-à-vis the male test animals, and the inducement of a wasting condition in the female test animals.
The researchers in this study believe early-life exposure to other chemicals and substances might similarly demonstrate disruption of human metabolism.
They also make an important observation: "Our most important findings center on the tendency to categorize environmental toxicants by allocating them to preconceived classes. Organophosphates are usually thought of as developmental neurotoxicants, but they obviously have other important targets that contribute to morbidity, including metabolic effects that can have a potential impact on obesity and diabetes.
"It is increasingly evident that adverse events in fetal or neonatal life, including chemical exposures like those studied here, can lead to misprogramming of metabolism, appetite, and endocrine status contributing ultimately to morbidities such as obesity and diabetes." Lassiter, et al, Exposure of Neonatal Rats to Parathion Elicits Sex-Selective Reprogramming of Metabolism and Alters the Response to a High-Fat Diet in Adulthood (2008).
They recommend further studies on the metabolic influence of environmental chemical exposures, which makes good policy and scientific sense. Thus, as good as animal bioassays are, and as much as I advocate their use in this comment, they can be designed to be even more effective.
Therefore, it is reasonable to examine animal bioassays for evidence of potential human harm, and to design regulatory structures around such analyses. These are not conclusions drawn in a vacuum, but based on long and validated experience with using animal bioassays to reasonably and prudently anticipate what chemicals or substances MAY be harmful to humans.
The authors of "Precaution In Applying The Precautionary Principle" appear to have raised a straw man in their essay. The evidence of harm from lead, as they acknowledge, is overwhelming, and they concede that its ban is reasonable. Apparently, without being quite so explicit, they want this type of decades long, overwhelming evidence to exist before any substance is banned or regulated. As noted above, such an extreme view is unnecessary, and perhaps even potentially dangerous to the health of humans, given the success of animal bioassays in identifying many potentially harmful substances and chemicals.
The authors seek to contrast the overwhelming evidence as to lead with the more limited evidence about the potential harmful aspects of phthalates.
Of course, as to phthalates, the evidence is much more intricate and complex because there are many types of phthalates (26 at my last count, and probably many more if one includes those that are chemically related or whose topology allows them to exert hormone-like effects); some of these chemicals have the potential for harm and some appear to be relatively benign.
The animal bioassay evidence involving the three permanently banned phthalates (DEHP, DBP, and BBP) and two of the temporarily banned phthalates (DINP and DnOP) noted by the authors in their column would certainly suggest that in fact caution is in order (see, for example, http://toxsci.oxfordjournals.org/cgi/content/abstract/58/2/350, http://toxnet.nlm.nih.gov/cgi-bin/sis/search/f?./temp/~ujtbew:1:animal, and http://en.wikipedia.org/wiki/Dibutyl_phthalate).
In contrast, there is certainly reason to question whether the "temporary" ban on one of the phthalates (DIDP) is reasonable, given the testing evidence and evaluations to date suggest it may not pose any potential risk (see http://www.didp-facts.com/RA and http://toxnet.nlm.nih.gov/cgi-bin/sis/search/f?./temp/~qhrVEU:1:animal).
Thus, the foundation of the legislation the authors excoriate is built not on some wild-eyed fear or paranoid delusion of the unknown, but upon a prudent judgment that there is a risk that should be avoided, risk demonstrated in animal bioassays.
In this particular example, animal bioassay testing would appear to support the permanent ban on three of the phthalates, support the temporary ban on two of the phthalates, and raise questions about the reasonableness of the temporary ban on one of the phthalates.
It is in this scientific and toxicological paradigm that regulation based on a narrower concept of the precautionary principle makes sense and provides a tool for the prudent avoidance of potential harm. The authors of the column, thus, do protest a bit too much [with apologies to Shakespeare, Hamlet, Act 3, Scene 2].