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Title: Pharmacoenvironmentology - A Component of Pharmacovigilance
Version: 3
Date: 3 May 2007
Reviewer: Kevin Woodward
Reviewer's report:
General
This is a timely article, which, with some revisions, will be of interest to both the
Pharmacovigilance community and to those in environmental activities. There are a number of
points the authors may wish to contemplate:
1. The authors use the term "Pharmacovigilance studies" in the abstract and elsewhere. However,
what they are often describing, or alluding to, is notification of adverse events rather than
"studies" which implies pharmacoepidemiology. I suggest changing "Pharmacovigilance studies"
to "Pharmacovigilance activities".
Suggestion acknowledged. The authors have changed the term “Pharmacovigilance studies”
to "Pharmacovigilance activities" in the abstract and elsewhere (introduction &
conclusion).
2. The authors also contend that Pharmacovigilance is concerned with "therapeutic
concentrations". This may be true in some countries but certainly in the EU or the US it extends
to misuse, abuse, overdose etc, as well as to environmental effects (regardless of whether the dose
was therapeutic or otherwise).
The word therapeutic concentration has referred to dose taken for prophylaxis, diagnosis,
or therapy of disease, or for the modification of physiological function. The
pharmacovigilance may include abuse, misuse but detection, assessment, understanding and
prevention of ADR has been the major activity under various national and international
Pharmacovigilance programmes (confer Safety Monitoring of medicinal Products –
Guidelines for setting up and running a Pharmacovigilance Centre, Uppsala Monitoring
Centre and WHO, 2000). The whole purpose of this paper is to generate opinion, so that
importance of ADR on environment during the process of drug development or once the
drug is marketed (as in post marketing surveillance).
According to current consensus and as per definition of WHO Collaborating Centre for
International Drug Monitoring (UMC, Uppsala, Sweden), Pharmacovigilance activities is
concerned with Monitoring of Adverse Drug Reactions(s) that is “a response to a medicine
which is noxious and unintended, and which occurs at doses normally used in man
(therapeutic doses). These reactions may be expected or unexpected. Authors have thus
embodied the definition of WHO which was proposed in 1972 (WHO Technical Report No
498) in the text. The basic definition includes all doses prescribed clinically, but is intended
to exclude accidental or deliberate overdose.
Confer:
1. Safety of medicines – A guide to detecting and reporting adverse drug reactions, WHO,
2002 (WHO/EDM/QSM/2002.2)
2. Dialogue in Pharmacovigilance – More Effective Communication, WHO Collaborating
Centre for International Drug Monitoring, UMC, Sweden, 2002)
3. The authors might want to consider including animal (veterinary) drugs in their paper,
especially as they mention animals in the text. If so, they might like to refer to and cite Boxall et
al., (2003) Environmental Science and Technology, Vol. 37, 286A-294A; Boxall et al., (2003)
Toxicology Letters, Vol 142, 207-218; Woodward, (2005) Journal of Veterinary Pharmacology &
Therapeutics, Vol 28, 171-184.
It’s a good suggestion by the reviewer if we add the suggested references in the text to make
the paper more extensive. Authors have now incorporated these references.
4. Under Discussion, I challenge the opinion that "50% to 90%" of a drug given to an animal or
human is excreted unchanged. Some drugs are poorly absorbed, some extensively, and some
poorly metabolized, and some extensively. Perhaps a sentence such as "When a human or animal
is given a drug orally, it may be well or poorly absorbed from the gastrointestinal tract. Clearly,
unabsorbed drug will pass with faeces into the environment. When humans or animals are given
drugs parenterally or orally, the drug may be metabolized to a greater or lesser extent and
excreted into the environment (including in exhaled air) as parent drug or metabolites, or as a
mixture of both.
The reviewer has rightly pointed out about the fate of drug after its administration. For
clear version and as per suggestion of the reviewer, we have changed the sentence as
mentioned by the reviewer himself.
5. The authors mention the effects of diclofenac on vultures and quote a review (Rahman and
Khan, 2006). However, the original articles reveal that this diclofenac arose not from use as a
human drug but in veterinary medicine - the vultures fed on carcasses of animals treated with
diclofenac (Prakash, 1999, Journal of the Bombay Natural History Society, Vol 96, 365-378;
Oaks et al. 2004, Nature, Vol 427, 630-633). This needs to be amended to reflect this.
In the original text, it is not mentioned that the diclofenac arose from use as a human drug.
However, the sentence has now been rewritten clearly with original references of Prakash
and Oaks. All these references were already mentioned in the paper of Rahman and Khan,
2006 as cross-references and hence were not cited in the original text again. However as
suggested by the esteemed reviewer, all these important and pioneer research papers have
now been incorporated.
6. I would include "veterinary drugs" in the list of PPCPs.
The reviewer’s has rightly pointed out. It is a part of PPCPs. Authors have not only
included veterinary drugs in their revised manuscript, but have also incorporated the
original paper of CG Daughton and TA Ternes in this regard.
7. The authors (correctly) suggest that in the EU, human medicines are subject to Phase I and
Phase II environmental risk assessment. They might like to add that veterinary medicines are also
subject to Phase I assessment (mainly an assessment of the amounts likely to enter the
environment) and Phase II (studies of effects on environmental organisms the extent of which
depends on the Phase I assessment. Medicines with high environmental entry e.g. those used in
aquaculture or extensively in cattle will require more Phase II testing than those used in
individual animals while companion animal products are likely to stop at Phase I.
It’s a good suggestion by the reviewer. We have incorporated his suggestion in our text.
8. Again the reference to "therapeutic" in the conclusions (change or delete). Also in the
conclusion, there is a reference to pharmacologists being involved in this activity. However, in
EU regulatory agencies and in companies like my own, we use ecotoxicologists or environmental
scientists. I'm not sure that most pharmacologists would have the correct background or training
for this work.
For monitoring of adverse events at normal doses for therapeutic purpose, we require the
help of pharmacologists (even veterinary pharmacologists). We need experts like
ecotoxicologists or environmental scientists for ecotoxicological / ecopharmacological
activities.
The Ecotoxicological studies defined species toxicity tests to predict impacts on
the more highly organized and complex structural/functional levels of communities or
ecosystem. Although most pharmaceuticals are designed to target specific metabolic
pathways in human and domestic animals they can have numerous often-unknown effects
on metabolic pathway of non-target organisms, especially invertebrates. Although many
non-target organisms share certain receptors with humans, effects on non-target organism
are usually unknown. It is important to recognize that for many drugs their specific modes
of action even in target species are also unknown. For these drugs its impossible to predict
what effects they might have on non target organisms without knowing the mode of action
coupled with not knowing the possible receptors, its impossible to design rational toxicity
procedures at the organism level. Thus pharmacologists with special training in causality
assessment of ADR could be of help. Moreover, in the present paper, authors specifically
tried to differentiate the same thing i.e. the role of pharmacologists, ecotoxicologists and
environmental scientists in reference to pharmacoenvironmentology, ecopharmacology and
ecotoxicology.
9. The authors might like to note that the 2007, Volume 41 of the Drug Information Journal was
dedicated to environmental effects of pharmaceuticals. They might like to bring their article up to
date by reference to article by Williams and Cook (Exposure to pharmaceuticals present in the
environment, Drug Information Journal, 2007, Vol 41, pp. 133-141) and by Sumpter
(Environmental effects of human pharmaceuticals, Drug Information Journal, 2007, Vol 41, 143147). The authors might also be interested in the following articles, which are relevant to their
publication: Henschel et al., 1997 Environmental hazard assessment of pharmaceuticals.
Regulatory Toxicology and Pharmacology, Vol 25, 220-225. Halling-Sorensen et al, 2000
Environmental risk assessment of antibiotics: comparison of mecillinam, trimethoprim and
ciprofloxacin. Journal of Antimicrobial Chemotherapy, Vol 46, Supplement S1, 53-58
In the text, we have integrated latest references, which have been suggested by the reviewer.
------------------------------------------------------------------------------Major Compulsory Revisions (that the author must respond to before a decision on publication
can be reached). The reference to vultures mentioned above is misleading and should be altered to
reflect the veterinary origins of the drug.
Revision has been made. The original references to vultures are added.
------------------------------------------------------------------------------Minor Essential Revisions (such as missing labels on figures, or the wrong use of a term, which
the author can be trusted to correct)
Most covered under general (above)
Revision of all those points suggested by the reviewer under “General” has been made.
------------------------------------------------------------------------------Discretionary Revisions (which the author can choose to ignore)
What next? Accept after minor essential revisions
Level of interest: An article of importance in its field
Quality of written English: Needs some language corrections before being published.
Quality of written English has also been ensured. All precautions are also made to make the
paper more clear, consistent and coherent after the referee’s extensive suggestions and
remarks.