The case for speciation. Speciation (i.e., valence state of the metal or its existence as an organic complex) can play an important role in toxicity. The cases of arsenic and mercury are instructive: Inorganic arsenic compounds are typically highly toxic. Dietary supplements that contain kelp or certain other nontoxic materials also contain high concentrations of essentially nontoxic organoarsenic compounds. Similarly, metallic mercury is relatively nontoxic, but inhaled mercury metal, methyl mercury, and similar organomercury compounds that can be concentrated in foods such as fish are highly toxic. Thus, workshop attendees concluded that tests for arsenic or mercury by themselves may not yield suitable data on which to base specifications. Further, reports of total arsenic or total mercury content may unnecessarily confuse consumers about the safety of the products they consume, leading the public to question the efficacy of regulatory standards.

Risk assessment. Participants agreed that several related factors must be considered when evaluating the acceptable rate and extent of exposure in vulnerable populations. Humans may experience degrees of environmental exposure to metals.

Another consideration is the duration of exposure. Long-term exposure to lead is associated with decreased intelligence quotient, and long-term exposure to organic mercury causes neuropathic effects. Concurrent exposure to both metals has not been well studied, but risk-assessment models suggest incremental risk.

Limits. If analysts do not separate metal forms (i.e., perform speciation) before undertaking metal analysis, the results will report the total of all forms detected (e.g., the method will report both inorganic and organic arsenic). Workshop participants did not reach a consensus about the level of detection required for each metal. A reasonable approach might involve the development of pharmacopeial specifications for the total amount of an individual metal at some limit (worst case), and requiring manufacturers to use speciation to justify a higher limit.

Analytical detection methods. Workshop participants decided that the following tests are probably suitable for compendial metal analysis: electrothermal atomic absorption spectrometry, inductively coupled plasma–optical emission spectrometry, inductively coupled plasma–mass spectrometry, and any other methods with similar specificity and sensitivity.

Use of reference materials. The revision of USP <231> will rely on reference materials to demonstrate recovery (i.e., precision and accuracy) during sample preparation and analysis. Reference materials also are needed to establish systems suitability and quantitation or detection limits, particularly when several technologies may be used to produce acceptable results.

Conclusion

Workshop participants advocated the revision of USP <231>. Further consideration of limits for various metals will be required. Arsenic, cadmium, lead, and mercury were singled out by participants for particular attention. Other metals used in manufacture or present in starting materials will be considered using a risk-based approach. USP will continue to work with stakeholders to update General Chapter <231> using harmonized approaches and a public process of review and comment.

Stefan Schuber, PhD, is director of scientific affairs, Anthony J. DeStefano, PhD, is vice-president, general chapters, Roger L. Williams, MD, is executive vice-president and chief executive officer, William F. Koch, PhD, is chief metrology officer, and Darrell R. Abernethy,* MD, PhD, is chief science officer, all at the United States Pharmacopeial Convention, 12601 Twinbrook Parkway, Rockville, MD 20852-1790, tel. 301.816.8184, dra@usp.org
. *To whom all correspondence should be addressed.