How do experts determine the safe level of a chemical?

“The main rule in toxicology is that ‘the dose makes the poison’. At some level, every chemical becomes toxic, but there are safe levels below that,” wrote Bruce Ames, who is the creator of the Ames Test which determines if a chemical is mutagenic.

Ames says that in the 1970s the prevailing thinking was that “we should assume that even low doses might cause cancer, even though we lacked the methods for measuring carcinogenic effects at low levels.” The assumption has never left, one need only to look at the ever-present Proposition 65 signs or listen to Vani Hari (aka the Food Babe).

At the time experts also assumed that:

1.  only a small proportion of chemicals would have carcinogenic potential
2. testing at a high dose would not produce a carcinogenic effect unique to the high dose; and
3. carcinogens were likely to be synthetic industrial chemicals.
   It is time to take account of information indicating that all three assumptions are wrong. – Bruce Ames, 2005.  (my emphasis)

Ames points out that our test for carcinogenicity of feeding animals near-fatal doses of the chemical is flawed because, “High doses can cause chronic wounding of tissues, cell death, and consequent chronic cell division of neighboring cells, which would otherwise not divide.”

How should a “safe” level be arrived at?

1. Determine a Point of Departure:

   This means to review the scientific data available on the toxicity of a compound and select the most sensitive endpoint. So if a chemical causes liver toxicity at a concentration of 1 mg/kg, kidney toxicity at 50 mg/kg and stomach ulcers at 0.1 mg/kg – the 0.1 mg/kg would be selected as the point of departure because if you pick a concentration that prevents stomach ulcers, you will by design also protect against the liver and kidney toxicity (because you need higher concentrations of the chemical to cause those). Furthermore, typically you are looking to pick a NOAEL (No Observable Adverse Effect Level) as a Point of Departure (POD), as this is the highest concentration of a “substance at which there are no biologically significant increases in frequency or severity of any effects in the exposed humans or animals.” (International Council on Harmonisation, 2011)

2. Determine how many modifying factors or uncertainty factors you should use.

The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) appendix 3 gives examples of the modifying factors to use, depending on what kind of study was conducted to determine the POD. Modifying (or uncertainty) factors provide a cushion to human exposure based on factors like which animal was used for the study, the duration of the study and whether the POD is a “No Observable Adverse Effect Level” (NOAEL) or LOAEL.

The “safe” level is really a concentration that would be highly unlikely to cause an adverse effect in even the most sensitive individuals. Using the modifying factors (in step 2 of appendix 3), this concentration results in a very conservative value. These “safe” levels are referred to as PDE (Permissible Daily Exposure), ADI (Acceptable Daily Intake), RfD (Reference Dose) and other things depending on the agency that is generating them, but they all mean the same thing: the level that would not be expected to produce an adverse effect. These values are expressed as either mg/day (where an adult body weight of between 50 and 70 kg is used as a “typical” body weight) or expressed as mg/kg body weight/day.