Monday, September 15, 2014

Acute Effects of Carcinogens

We tend to think of chemicals that cause cancer as doing so over a relatively extended period of time.

Indeed, the exposure metric used for evaluating this risk by the EPA is often the Lifetime Average Daily Dose (LADD).   Specifically, we are told in an EPA document on the subject of pesticide risk assessment:  that:

“…If the endpoint is cancer, the [Average Daily Dose] ADD must be amortized over the duration of a lifetime using the calculation for a [Lifetime Average Daily Dose](LADD)  . An equation that can be used to calculate LADD values is presented below:

LADD = ADD * (F/365) * (ED/LT)) 
  • LADD = ADD amortized over an individual's lifetime (e.g., mg/kg/day);
  • F = frequency of exposure events or the number of days exposed to the pesticide of concern per annum (days/year);
  • ED = exposure duration throughout a lifetime or the number of years exposed to a specific chemical throughout an individual's lifetime (years); and
  • LT = anticipated lifetime of an individual in the exposed population of interest (years…”

Thought of this way the risk of any particular chemical can be considered as a virtual “cup”  that is filled to various levels of the carcinogen of interest as one goes through life.  The more the cup is filled the greater the chance of getting cancer from the exposure.  

This approach essentially ignores any dose rate effect for carcinogenicity which may or may not be correct; however, the point of this blog is to highlight the fact that at least some carcinogens may exhibit adverse health effects, from acute or even bolus exposure that may or may not relate to their ability to cause cancer in animals or humans as part of an LADD.  

A case-in-point that recently came to my attention is dimethyl and diethyl nitrosamines. 

Everyone knows and readily accepts that these compounds are powerful liver carcinogens in laboratory animals.  Indeed, many or most consider them to be putative human carcinogens and their risk is managed for the most part on this basis; however, little has been known or studied relative to their ability to cause acute injury.   

In November of 1976 the EPA published a comprehensive (228  page) report entitled:  Scientific and Technical Assessment Report on Nitrosamines.  EPA-600/6-77-001.  The entire report is available online as a PDF imagine, just put the EPA report number into Google.  Among many other things, the report addresses the issue of acute toxicity of nitrosamines. To quote this report:  “The potency of N-nitroso compounds in causing acute tissue injury and death varies considerably (Table 3-1).”    Table 3-1 clearly shows that dimethyl and diethyl nitrosamine are considered the most reactive compounds in the nitrosamine series and to quote the report, as the most “reactive compounds produce hemorrhagic destructive lesions at the site of contact…” [emphasis added]   The report goes on further in the same paragraph: “Spills have led to irritation of the eyes, lings and skin.”

The report also provides some insight as to why acute toxicity has not been studied much by stating that the hepato-carcinogenicity of these compounds is so striking that the study of the acute effect(s) has been essentially ignored.  From the above however it appears that acute contact site toxicity of the respiratory tract for inhalation and the skin for dermal exposure are likely.

This blog has covered various aspects of bolus exposures in the recent past.   The lesson from the above information on nitrosamine is clear; if you are dealing with bolus exposure to putative carcinogens you need to address their acute as well as their chronic toxicity potential.

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