Perchlorate Fireworks

Regular visitors to VanishingZero are probably aware of the concern expressed by many toxicologists and other scientists over attempts to regulate perchlorate, a naturally occurring environmental constituent, to levels below those required for environmental arsenic.  This despite that fact that there have been no reliable data found to connect trace (parts per billion) perchlorate exposures to any public health event or incident.  In the view of many, the perchlorate debate has evolved into a political issue that in some quarters is being pressed at the expense of the use of sound science in determining public policy.  A recent note in the October 2006 issue of  "Mainstream," published by the American Water Works Association demonstrates a consequence of the mindest "If you can detect it, you should regulate it." Titled "Perchlorate Fears Douse Fireworks," the front-page blurb said the following:

"Massachusetts' adoption of a maximum contaminant level (MCL) of 2 ppb for perchlorate in late July apparently doused plans for fireworks at the annual Harwich Cranberry Festival on Cape Cod in September.

Perchlorate, a chemical that disrupts thyroid functions, is used as a propellant for fireworks and persists in water for decades.

Raising concerns about contamination of the aquifer used for the city's water supply, water commissioners would have asked the festival for a $10 million bond for caonamination cleanup, but Harwich selectmen voted to ban any perchlorate-based fireworks displays in the aquifer's recharge area.

The fireworks company offered to switch to a nitrates-based display but then found its insurance company wouldn't cover environmental contamination."

Data Quality Act Court Case

The 17 March 2006 issue of Science reported on a federal appeals court ruling that the public cannot sue federal agencies over an agency's compliance with what has become a controversial law on the quality of scientific data. The Data Quality Act (DQA) has required agencies to set standards to ensure the quality of information they disseminate, such as the toxicological effects of chemicals. It allows petitions from critics who take the position that such standards have not been met; denial of a petition allows no recourse. 

A Virginia federal district court, supported by the U.S. Court of Appeals, rejected a bid by the Salt Institute et al. to obtain unpublished data from a study on salt intake funded in part by the National Heart, Lung, and Blood Institute. The conservative panel of judges found that the DQA "does not create any legal right to information or its correctness."  Therefore, the plaintiffs lacked legal standing to pursue their case.  In some quarters, the decision is taken to mean that the intent to enforce the DQA is being undermined.

More detail is available at  www.sciencemag.org

Microdosing and the Vanishing Zero

The July 2005 issue of Drug Discovery News featured an interesting editorial (p. 8) by Randall Willis on the topic of microdosing in the "nether region between preclinical and clinical testing - Phase 0."  To some who have been alerted to the WSJ article of July 25, 2005 (posted here elsewhere), the regimen involved here may appear to intersect the conditions being used to study the effects on human health of ultra trace agents in the environment, namely parts per billion or smaller.  Microdosing simply involves the administration of sub-pharmacological or sub-therapeutic doses - micrograms - of a drug candidate to humans.  At least one study seems to indicate that microdose data are largely predictive of therapeutic dose response.            

Mainstream chemists interested in the nuances of chemical analysis would appreciate the fact that these protocols are only possible because of the technical advances in instrument detection limits that allow "almost single molecule detection."  Greater complexity comes from a realization that "sub-dosing" involves microgram quantities of chemical agents, similar to many environmental exposure levels (ppb).  Compare that to therapeutic dosages of an agent like perchlorate (historically used in treatment of Graves' disease) that has been administered at dosages of hundreds of milligrams per day, thousands of times higher than environmental exposure levels.  Small wonder that uncertainty drives many an environmental debate.

More on the topic:  www.drugdiscoverynews.com.

Minute Dose Health Risk Issues

The July 25, 2005 edition of the Wall Street Journal featured a front page article by Peter Waldman on the issue of the effects of minute doses of chemical agents on hormonal processes that impact human health. The evaluation of effects of substituents in amounts as low as parts per trillion "challenges an axiom of toxicology stated by the Swiss chemist Paracelsus nearly 500 years ago:  The dose makes the poison." 

There are many complicating factors. Some chemical agents seem to require the presence of a secondary agent in order to manifest biological effects. Accurate analytical measurement of part per trillion levels of analytes presents significant challenges. And the possibility or likelihood of natural occurrence of some agents (such as perchlorate) commonly regarded as "industrial chemicals" further complicates the "risk vs. benefit" debate. 

For more information go to  www.wsj.com.

How does EPA determine drinking water exposure guidelines?

Both the scientific community and the public need to develop a thorough understanding of the mechanism used to calculate the guidelines (as Oral Reference Dose, or RfD) used to limit drinking water exposure levels. The EPA can use a variety of uncertainty factors in the derivation of the RfD. These uncertainty factors are based subjectively on study methods, toxicological data bases, and other information, and typically are given values of 1, 3 or 10. Whether these factors are fairly applied on a systematic basis can be a subject of considerable debate.

One important issue is determining, for a given exposure situation, what is the critical endpoint in the critical study. It is in the EPA's authority to choose that critical data point. In addition, if there is a dose at which no adverse effects are observed, this becomes the NOAEL (no-observed-adverse-effect-level) upon which the reference dose (RfD) is based. Otherwise, the RfD is based upon the LOAEL (lowest-observed-adverse-effect-level).

The following relationships can be used to derive the RfD, which in turn is translated into a Drinking Water Equivalent Level (DWEL) related to individual body weight.  The DWEL is found by multiplying the RfD times the body weight in kg , divided by the volume of water consumed per day.  This in turn is equal to the term below, in which the U factors are typically 1, 3 or 10 (greatest uncertainty).

NOAEL or LOAEL (mg/kg-day)                                                                     UFl x UFa x UFh x UFd x UFs                        

where:

UFl  =  the LOAEL uncertainty factor, intended to compensate for the use of a LOAEL rather than a NOAEL as the basis for the RfD

UFa = interspecies uncertainty factor, intended to account for uncertainty involved in extrapolating from animal (e.g. rat) to humans.

UFh = intraspecies uncertainty factor, intended to account for variation in response among the human population for the end-point in question, with the particular intention of protecting sensitive subpopulations.

UFd = database uncertainty factor, essentially the completeness of the overall database especially as relates to the critical study.

UFs = subchronic to chronic uncertainty factor, intended to account for the uncertainty involved inextrapolating from a less-than-chronic NOAEL to a chronic NOAEL when a chronic NOAEL of sufficient quality is not available. [Note - this factor was not used by the EPA in the derivation of an RfD for perchlorate because the mechanism of perchlorate action is such that the effects of subchronic exposure fully account for the effects of chronic exposure.]