Connecting Risk and Safety for Toxic Substances
J. Thomas Pierce, MBBS PhD
International University of Health Sciences
Evaluating toxicity from qualitative and quantitative standpoints
• This is an applied mathematical approach to generalize beyond specifics of individual compounds and variable test batteries to groups of chemicals;
• It employs a connector between risk and safety that further aids discussion.
Table 1
Levels of Biological (Pharmacological) Inquiry
1 Populations
2 Closely intercommunicating groups of organisms (special needs groups,
neighborhoods)
3 Mothers and fetuses
4 Whole organisms (mature or immature)
5 Organ systems (CNS, PNS, heart, lungs, kidneys, adrenals, muscles in exercise)
6 Organs (brain, heart, muscles, liver, kidneys, endocrine glands)
7 Groups of directly intercommunicating cells (neurons, glia, Schwann cells)
8 Cells
9 Subcellular structures (microsomes, mitochondria, nucleus)
10 Groups of interacting molecules (genome, enzyme systems, drug receptors, internal
signaling mechanism)
11 Molecules (genes, enzymes, receptors)
Source: Uruquart (2004)
No Favorites
• We are more interested in the scope of effects than picking favorites among even the more serious effects;
• We like to think this is a holistic approach.
Toxicity Grades
0= no adverse event, or within normal limits
1 = mild adverse event
3 = severe and undesirable adverse event
4 = life-threatening or disabling adverse event
5 = death related to adverse event
Order the results in a logical manner
We typically list them in descending order as
X1 > X2 > X3 > …. X n
Toxicity Index depends on
• The mixture or commercial product’s TI score (calculated) as the weighted sum of the ordered toxicity grades
n• TI = Σ Wi Xi
• i = 1where• j -1• WI = π (X j + 1) -1
• j = 1
Toxicity Index is still ‘qualitative’
• Numbers being numbers there is no way to say that a heart attack is any more or less important than colon cancer;
• We leave this section at the level of summation;
• So why did we show the sigma and pi functions – mostly because someone may come along later and improve on this
Published risk estimates accompanying concentrations from agencies and boards
Published Risk Estimates
• DOD, Emergency standards 1 E -3
• ACGIH, PEL, most occupational 1E - 4
• USEPA, Europeans 1E -5
Some things happen all the time, others not so much…
• Clearly, at less than one in a thousand, these aren’t frequent events at the concentration range studied but they are still important;
• We do some math gymnastics to take the logarithm of the power of 10 and then subtract it from the number 10
• Thus 1 E -3, is transformed into
• 10 – 3 = 7 (that’s high in terms of 1-10
More subtraction to get a risk number
• Often the USEPA standard is based on 1E -5;
• So here we would derive 10 -5 = 5, a more intermediate value;
• I didn’t list it here, but what if a risk were rated at 1E – 9 (one in a billion);
• We’d get 10 – 9 = 1 (smaller risk).
• We define our calculation as the TRU© - Toxic Risk Unit.
Toxic Risk Unit ©
• You’ve seen how we get it from a log transform and a simple subtraction,
• But, there is more –
• We use it to give it a companion Toxic Safety Unit (TSU©);
• TRU + TSU always equals 10;
• This means when TRU goes down that TSU goes up.
Let’s go back to 1 in a thousand…
10
• TRU = 7; TSU = 3 TSU
1TRU
110
The Colors aren’t accidental
10 1TSU
TRU 101
Small moves over here aren’t very satisfactory
Moving around Here offers modest gains but it typicalOf many regulatory changes
This is wherealternatives need to exist
The TSU© rating is harder to explain
• But it captures our imagination in terms of what I call ‘assurance of safety;’
• Just remember it is always tied to the risk estimation by;
• TRU + TSU = 10, and;
• That the TRU originated from published risk estimates.
How to tie together the qualitative (TI) and quantitative values (TRU/TSU©)
• Each has a particular quality and value;
• Both need to be consulted;
• No one has an exact formula to that end at present.