UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460

OFFICE OF PREVENTION, PESTICIDES

AND TOXIC SUBSTANCES

  SEQ CHAPTER \h \r 1 MEMORANDUM

7/2/2007

SUBJECT:	The Mode of Action and Human Relevance of HPPD-Inhibiting
Herbicides (D 341612)

FROM: 	Hazard Science Policy Council

		Vicki Dellarco (Co-Chair)

Ray Kent (Co-Chair)

William Burnam

Jess Rowland

Elizabeth Mendez (invited member)

		Tina Levine (HED Director)

TO:		PV Shah (Acting Branch Chief, RAB1)  SEQ CHAPTER \h \r 1   SEQ
CHAPTER \h \r 1 

		Health Effects Division (7509P)

PURPOSE OF MEETING:

	The HED HASPOC met on June 28, 2007 to discuss (i) whether
HPPD-inhibiting pesticides shared a common effect and common mechanism
of toxicity; (ii) species differences in the animal toxicity studies,
and species differences in the expression of TAT (tyrosine
aminotransferase), (iii) the human experience with genetic disorders of
tyrosinemia and treatment with HPPD inhibiting drugs (e.g., Nitisinone);
and (iv) whether the rat ocular toxicity is an appropriate model  in our
 health risk assessments as a regulatory endpoint. 

HASPOC agreed that there was evidence of an association of HPPD
inhibition leading to induced tyrosinemia (elevated plasma tyrosine
levels) and ocular effects.  However, because humans have an efficient
metabolic process to handle excess plasma tyrosine levels and given the
clinical experience with HPPD-inhibiting drugs, it is unlikely that
exposure to pesticide residues will result in tyrosinemia-related
toxicity in humans as observed in the rat (the susceptible species).
Accordingly, although HPPD inhibiting-herbicides may share a common mode
of action, exposure to these herbicides are unlikely to induce adverse
health outcomes in humans.    Thus, there is not a likely human health
impact to indicate the need for a cumulative risk assessment.  OPP
should depart from this science policy where new facts or circumstances
warrant, however. 

 The following boilerplate language is suggested for the HPPD-Inhibiting
herbicides. 

Pesticide X belongs to a class of herbicides that inhibit the liver
enzyme 4-hydroxyphenylpyruvate dioxygenase (HPPD), which is involved in
the catabolism (metabolic breakdown) of tyrosine (an amino acid derived
from proteins in the diet).  Inhibition of HPPD can result in elevated
tyrosine levels in the blood, a condition called tyrosinemia. 
HPPD-inhibiting herbicides have been found to cause a number of
toxicities in laboratory animal studies including ocular, developmental,
liver and kidney effects.   Of these toxicities, it is the ocular effect
(corneal opacity) that is highly correlated with the elevated blood
tyrosine levels. In fact, rats dosed with tyrosine alone show ocular
opacities similar to those seen with HPPD inhibitors.  Although the
other toxicities may be associated with chemically-induced tyrosinemia,
other mechanisms may also be involved. 

There are marked differences among species in the ocular toxicity
associated with inhibition of HPPD.  Ocular effects following treatment
with HPPD inhibitor herbicides are seen in the rat but not in the
mouse.  Monkeys also seem to be recalcitrant to the ocular toxicity
induced by HPPD inhibition.  The explanation of this species-specific
response in ocular opacity is related to the species differences in the
clearance of tyrosine.  A metabolic pathway exists to remove tyrosine
from the blood that involves a liver enzyme called tyrosine
aminotransferase (TAT). In contrast to rats where ocular toxicity is
observed following exposure to HPPD-inhibiting herbicides, mice and
humans are unlikely to achieve the levels of plasma tyrosine necessary
to produce ocular opacities because the activity of TAT in these species
is much greater compared to rats.   Thus, humans and mice have a highly
effective metabolic process for handling excess tyrosine. 

HPPD inhibitors ( e.g., Nitisinone) are used as an effective therapeutic
agent  to treat patients suffering from rare genetic diseases of
tyrosine catabolism.  Treatment starts in childhood but is often
sustained throughout patients lifetime.   

The human experience indicates that a therapeutic dose (1 mg/kg/day
dose) of Nitisinone has an excellent safety record in infants, children
and adults and that serious adverse health outcomes have not been
observed in a population followed for approximately a decade.   Rarely,
ocular effects are seen in patients with high plasma tyrosine levels;
however these effects are transient and can be readily reversed upon
adherence to a restricted protein diet.  This indicates that an HPPD
inhibitor in it of itself cannot easily overwhelm the tyrosine-clearance
mechanism in humans. 

Therefore, exposure to environmental residues of HPPD-inhibiting
herbicides are unlikely to result in the high blood levels of tyrosine
and ocular toxicity in humans due to an efficient metabolic process to
handle excess tyrosine. Single chemical risk assessments for which the
hazard endpoint selected is from a rat toxicity study and the effect
observed is ocular opacity due to tyrosinemia should be considered worst
case.

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