Toxicology & How to Calculate the First Safe Dilution

Matthew D. Reed, PhD, DABT, ATS led two workshops at AAHP’s recent Safety Summit, providing an in-depth introduction to the principles of toxicology and risk assessment, an appraisal of the role of toxicological studies in pharmaceutical development, and a review of the methodology for assigning first safe dilution levels.

In assessing risk, Dr. Reed said one must consider:

• Whether a substance causes adverse health effects. (This can be evaluated through an analysis of the substance’s structure and expected activity, or in vitro tests, bioassays or epidemiology. Much of this information may be available in toxicology literature);
• The relationship between the dose and the response, including factors such as susceptibility, and special population considerations;
• Exposure assessment, including the type, level, and duration experienced or anticipated.

From these considerations, the risk can be characterized based on the nature and anticipated incidence of adverse events, how clear and strong the evidence is, and the confidence level of the evaluation.

Dr. Reed pointed out that because human exposure information is too often limited, animal data is the primary basis for most quantitative risk assessments; these must be extrapolated to predict human health risk. He noted one usually chooses the most robust data information with adverse effects at the lowest levels of exposure from studies using the most relevant route of exposure. Of course, there are two general assumptions: animal models will predict safety/toxicity and high doses will maximize model (animal) sensitivity to detect effects. These underlie the information that must be utilized when attempting to determine the most concentrated homeopathic attenuation (the First Safe Dilution or FSD) that is appropriate for OTC sale.

Dr. Reed presented and endorsed the model the HPCUS uses to determine the FSD. For these determinations, the HPCUS Toxicity and Safety Committee considers up to seven categories of information:

• Single Dose (Acute) Toxicity
• Repeat Dose (Chronic) Toxicity
• Genotoxicity, Carcinogenicity, Reproductive and Developmental Toxicity
• Local Tolerance
• Antigenicity
• Immunotoxicity
• Addiction Potential

To determine FSD, HPCUS begins with acute toxicity data from the literature to determine the dilution that would produce a 100-fold margin of safety associated with the accidental ingestion by a 10 kg child of a maximum dose of 30 ml or 16.2 g (250 one-grain size tablets), whichever provides a greater dose, of the substance under consideration. This perspective is based upon a worst-case situation in which a very young child accidentally ingests an entire normal consumer package.

Putting the calculation in words: the FSD is determined by using the maximum amount due to accidental ingestion, multiplied by the presence (percentage) of the toxic substance of concern in the starting material; this arithmetic product is then divided by the minimum quantity known to trigger an adverse event. The result is expressed in scientific notation, and the exponent is rounded up to the nearest integer; to that integer, the quantity “2” is added. This result is the FSD (decimal attenuation); this rounding up and the addition of the quantity “2” ensures that the FSD is at least 100 times less concentrated than the calculated lowest quantity that might cause an adverse event in a 10 kg child who ingested an entire consumer package.

The formula looks like this:

		(maximum accidental      X     (% content of substance of ingestion amount)                   concern in starting material)
FSD *	=	________________________________________________
		(minimum quantity that triggers an adverse event)

 

* when the answer is expressed in scientific notation, the exponent is rounded up to the nearest integer followed by the addition of “2”.

For repeat or chronic exposure, the committee uses the Permissible Daily Exposure (PDE) based upon the No Observable Adverse Event Level (NOAEL). An important toxicological parameter, NOAEL is defined as the highest dose/exposure that does not cause biologically important increases in the frequency or severity of effects between the exposed population and the appropriate control.

While minimal toxic effects may be observed at this level, they are not considered to endanger human health or be precursors of serious events. The NOAEL is not risk free, thus the calculations include factors (that decrease the result of the calculation) based on inherent uncertainties due to extrapolation of animal data to humans, variability between individuals, different study period lengths, potential severe toxicity, and the use of Lowest Observable (Adverse) Event Level or LO(A)EL data when NOAEL information is unobtainable.