Work by an honest toxicologist–Ed Calabrese

Ed Calabrese is a prominent and contrarian toxicologist who adheres to the rule the dose makes the poison (or the carcinogen).

He also is an eloquent advocate for the concept of hormesis–low doses can have beneficial effects for a substance that may be toxic or eve lethal at high doses.

IN the past we have displayed Ed’s work to expose the misconduct with regards to the creation of the no threshold linear model for radiation effects. Ed doesn’t accept no threshold–same here.

He also believes that many things display a hormetic effect–benefits at low doses when toxic at high does–well many of the drugs I use are just like that. Tylenol will wipe out your liver if you take more than 140 mg per Kilogram of body weight in an acute dose. Different dynamics in chronic overdosing, but still toxic. And we have an antidote.

In Emergency Medicine we see the phenomenon all the time–pharmacology is the flip side of toxicology and dosing is about finding the level of benefit with injury or harm. It’s all about finding the sweet spot.

Ed is my hero because he is fighting back on the inanity of no threshold linear tox. He also says that the carcinogenicity studies are flawed–big dose tox on mice and rats is not the way to determine human carcinogenicity and at what level–the one hit theory is lame, maybe even lame-brained. I think so. Ed does to–we see chemophobia all the time, encouraged by improper toxicology methodology.

Here is a new paper by Ed on cancer research and tox. Received it a few days ago.

Cancer risk assessment: Optimizing human health through linear
dose–response models

Edward J. Calabrese a,*, Dima Yazji Shamoun b, Jaap C. Hanekamp c
a School of Public Health & Health Sciences, Department of Environmental Health Sciences, Morrill I N344, University of Massachusetts, Amherst, MA
01003, USA
b Mercatus Center, George Mason University, 3434 Washington Blvd., Arlington, VA 22201, USA
c Roosevelt Academy, Lange Noordstraat 1, NL-4331 CB Middelburg, The Netherlands
Article history:
Received 27 February 2015
Accepted 18 April 2015
Available online 24 April 2015
Risk assessment
Precautionary principle
This paper proposes that generic cancer risk assessments be based on the integration of the Linear Non-
Threshold (LNT) and hormetic dose–responses since optimal hormetic beneficial responses are estimated
to occur at the dose associated with a 10−4 risk level based on the use of a LNT model as applied to animal
cancer studies. The adoption of the 10−4 risk estimate provides a theoretical and practical integration of
two competing risk assessment models whose predictions cannot be validated in human population studies
or with standard chronic animal bioassay data. This model-integration reveals both substantial protection
of the population from cancer effects (i.e. functional utility of the LNT model) while offering the
possibility of significant reductions in cancer incidence should the hormetic dose–response model predictions
be correct. The dose yielding the 10−4 cancer risk therefore yields the optimized toxicologically
based “regulatory sweet spot”.
© 2015 Elsevier Ltd. All rights reserved.
1. Introduction
The assessment of cancer risks from exposure to ionizing radiation
and chemical carcinogens by regulatory agencies worldwide
is typically performed via the use of linear at low dose modeling.
The linear non-threshold (LNT) approach for cancer risk assessment
was first proposed for cancer risk assessment by the U.S.
National Committee for Radiation Protection and Measurement
(NCRPM) in 1958, following the recommendation of the U.S. National
Academy of Sciences (NAS) Biological Effects of Atomic
Radiation (BEAR) I Genetics Panel to switch from a threshold to a
linear model for assessing genomic risk from ionizing radiation in
1956 (Jolly, 2003; Whitemore, 1986).
The LNT approach was later adopted by regulatory agencies starting
in the late 1970s assessing risks for chemical carcinogens in all
media (e.g. air, water, food and soil) (National Academy of Sciences
(NAS), 1977). The initial transition from the threshold to the LNT
approach in the mid 1950s was made prior to the discovery of DNA
repair, adaptive responses with chemical mutagens and ionizing radiation,
apoptosis, pre-conditioning and the resurgence of the
hormetic concept, all of which could affect the shape of the dose
response in the low-dose zone. The clarification of different mechanisms
of action for carcinogens has encouraged the development
of cancer risk assessment methods that incorporate knowledge of
species specificity and threshold. These approaches are often employed
by the U.S. EPA and FDA and most European authorities for
non-genotoxic carcinogens (Page et al., 1997; Whysner andWilliams,
1992; Williams, 2001; Williams et al., 2012).
These developments have challenged the theoretical and mechanistic
basis of the LNT, along with the recognition that
epidemiological methods are in effect not capable of detecting risks
below twice the normal background (Taubes, 1995). Furthermore,
the massive mega-mouse study that used 24,000 animals was only
able to estimate risk at the 1% level (ED01 study) (Bruce et al., 1981).
Similar limitations were reported for a cancer bioassay study with
>40,000 trout (Bailey et al., 2009). These methodological limitations
along with the more recent developmental insights on the
plethora of adaptive mechanisms that act at low doses have revealed
limitations of the LNT model.
2. Developments
The dose–response model that has been shown to have biological
plausibility, especially in the low dose zone, is hormesis, a
biphasic dose–response. Current interest in hormesis can be traced
back to the research of Thomas Luckey on radiation hormesis (Luckey,
1980) and on chemical hormesis by Tony Stebbing (Stebbing, 1982).

These researchers stimulated the electric power utilities of Japan
* Corresponding author. School of Public Health & Health Sciences, Department
of Environmental Health Sciences, Morrill I N344, University of Massachusetts,
Amherst, MA 01003, USA. Tel: +1 413 545 3164; fax: +1 413 545 4692.
E-mail address: (E.J. Calabrese).
0278-6915/© 2015 Elsevier Ltd. All rights reserved.
Food and Chemical Toxicology 81 (2015) 137–140
Contents lists available at ScienceDirect
Food and Chemical Toxicology
journal homepage:


One response to “Work by an honest toxicologist–Ed Calabrese

  1. Methotrexate is another example. In small doses it is used to treat Rheumatoid Arthritis and some other kinds of arthritis. At higher and more toxic levels it is used to treat cancer.

    Yes, you are so right about paracetamol (the word we use in Australia for the ingredient of Tylenol). The advice is: no more than 8 tablets per day because it is toxic for the liver.

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