PYRROLIZIDINE ALKALOIDS
Overview
Functional Class
Food Contaminant
NATURALLY_OCCURRING_TOXICANT
NATURALLY_OCCURRING_TOXICANT
Evaluations
Evaluation year: 2015
Comments:
The Committee was unable to complete its toxicological evaluation at the present meeting. The full evaluation was published in 2020.
The Committee noted that most studies of toxicity, and of occurrence of PAs
in food, were focused on the 1,2-unsaturated PAs. The Committee concluded
that while the saturated PAs could not elicit toxicity via the same mechanism as
1,2-unsaturated PAs, their toxicity in humans could not be excluded, but there
were insufficient studies for evaluation. The Committee therefore decided to focus the evaluation on the 1,2-unsaturated PAs. Exposure to 1,2-unsaturated PAs has been associated with a wide range
of effects, with rats being the most sensitive species studied. In vitro studies
on metabolic activation indicate that humans are also likely to be sensitive.
Laboratory studies have identified the liver as the most sensitive organ in rats,
following both short-term and long-term administration of a number of PAs.
The 1,2-unsaturated PAs that have been tested form DNA adducts and are
mutagenic. Based upon an understanding of their chemistry and metabolism,
it is concluded that this property is common to all 1,2-unsaturated PAs, albeit
with differing potencies, and that it is relevant to humans. PAs appear to be
antimitotic in hepatocytes. A number of 1,2-unsaturated PAs have been shown to
be carcinogenic in rodents, primarily causing haemangiosarcomas in the liver, i.e.
originating in the endothelial cells rather than the hepatocytes. Carcinogenicity
has not been investigated in case studies of human poisoning with PAs. The Committee considered that derivation of a health-based guidance
value for PAs was not appropriate in view of the genotoxic mode of action.
From the carcinogenicity data in rats, a BMDL10 of 182 µg/kg bw per day for
liver haemangiosarcoma in female rats.
Intake:
The Committee calculated MOEs between the BMDL of 182 µg/kg bw
per day and mean and high-percentile (90th, 95th or 97.5th, depending on the
study) chronic exposure estimates for children and adults from consumption of
honey and tea, separately. As several national estimates of dietary exposure were available for each food, MOEs were calculated using a range from the lowest lower-bound mean or high-percentile dietary exposure to the highest upper-bound mean or high-percentile dietary exposures. This range takes into account the
uncertainty in measurements of 1,2,-unsaturated PAs and their N-oxides and the
variability in their concentrations and national estimates of food consumption. For adult consumption of honey, mean and high-percentile chronic
dietary exposures to 1,2-unsaturated PAs are in the range 0.00002 to 0.0039 µg/
kg bw per day and 0.005 to 0.026 µg/kg bw per day, respectively. These dietary
exposures equate to MOEs in the range 46 000 to 9 million for mean exposures
and 6900 to 36 000 for high-percentile exposures. For children consuming
honey, the ranges of mean and high-percentile chronic dietary exposures to
1,2-unsaturated PAs are 0.00001 to 0.013 µg/kg bw per day and 0.006–0.082 µg/
kg bw per day, equating to MOEs in the range 14 000 to 18 million for mean
exposure and 2200 to 30 000 for high-percentile exposure. For adult consumption of tea, mean and high-percentile chronic dietary
exposures to 1,2-unsaturated PAs are in the range 0.0013 to 0.13 µg/kg bw per
day and 0.01 to 0.26 µg/kg bw per day, respectively. These dietary exposures
equate to MOEs in the range 1400 to 140 000 for mean exposure and 700 to
18 000 for high-percentile exposure. For children consuming tea, the range of
mean and high-percentile chronic dietary exposures to 1,2-unsaturated PAs are
0.005 to 0.018 µg/kg bw per day and 0.027–0.076 µg/kg bw per day, respectively.
These dietary exposures equate to MOEs in the range 10 000 to 36 000 for mean
exposure and 2400 to 6700 for high-percentile exposure. It should be noted that estimates of dietary exposure to 1,2-unsaturated
PAs and their N-oxides from tea consumption are likely to be overestimates, as
concentration data from herbal teas have been combined with information on
total tea consumption.
The Committee noted that there is currently insufficient information to determine MOEs for other
food types or for the total diet.
Meeting:
80
Report:
Tox Monograph: