IJT - CIR - February 2024 - 17S

Becker et al.
17S
Subchronic Toxicity Studies
Oral. In a study on the effects of Humulus lupulus (hops)
extract on high-fat diets, male C57BL/6J mice (n = 10/group)
were fed a normal diet, a high-fat diet, or a high-fat diet
supplemented with 2 or 5% ofvarious Humulus lupulus (hops)
extracts for 20 weeks.76 The high-fat diet was supplemented
with one of the following: aqueous Humulus lupulus (hops)
extract, ethyl acetate-soluble fraction ofthe aqueous Humulus
lupulus (hops) extract, ethyl acetate-insoluble fraction of the
aqueous Humulus lupulus (hops) extract, methanol-soluble
fraction of the ethyl acetate-insoluble fraction of the aqueous
Humulus lupulus (hops) extract, or methanol-insoluble fraction
of the ethyl acetate-insoluble fraction of the aqueous
Humulus lupulus (hops) extract. There were no mortalities or
adverse effects reported for any group. The addition of any
Humulus lupulus (hops) extract reduced the effects of the
high-fat diet on weight gain. The weights of livers and
mesenteric and epididymal adipose tissues of mice fed the
supplemented high-fat diets were similar to that of the controls,
as were plasma glucose levels, at the end of the test
period; the extract had no additional effect on the effects ofthe
high-fat diets.
Developmental and Reproductive Toxicity
(Dart) Studies
Developmental and reproductive toxicity data on Humulus
lupulus (hops)-derived ingredients were not found in the
published literature and no unpublished data were submitted.
Genotoxicity Studies
In Vitro
Humulus Lupulus (Hops) Extract. An aqueous Humulus Lupulus
(Hops) Extract (10 to 400 mg/µL in ethanol) was weakly
mutagenic (a 2- to 4-fold increase in induced revertants
compared with controls) in Salmonella typhimurium (strains
TA98 and TA100), with or without metabolic activation.77 No
further details were provided.
A Humulus Lupulus (Hops) Extract (0, 1000, 2500, 5000,
7500, and 10,000 µg/plate; extract solvent not specified; water
control) was not mutagenic in S. typhimurium (strains TA98
and TA100) or Escherichia coli (strain pKM101), with or
without metabolic activation.78 The positive and negative
controls yielded the expected results.
An Ames test was performed on a product mixture
containing 5% Humulus Lupulus (Hops) Extract (extracted
in water/glycerin 50/50) at 10% in deionized water (effective
concentration of .5% hops) with and without metabolic
activation using S. typhimurium (strains TA97a,
TA98, TA100, TA201, and TA1535).79 The test substance
was not mutagenic in this assay with or without metabolic
activation.
Carcinogenicity Studies
Carcinogenicity data on Humulus lupulus (hops)-derived ingredients
were not found in the published literature and no
unpublished data were submitted.
Other Relevant Studies
Estrogenic Activity
Historically, there is circumstantial evidence of potential estrogenic
activity connected to Humulus lupulus (hops) exposure,
including menstrual disturbances reported to be
common among female Humulus lupulus (hops)
harvesters.80,81 In an investigation ofthe reported observation
that women who normally live " a distance " from hop gardens
regularly begin to menstruate two days after arriving to pick
hops, it was reported that hops contain " the equivalent of20 to
300 μg estradiol/g " .49 Humulus lupulus (hops) extracts have
been reported to reduce hot flashes in menopausal women and,
in Germany, hops baths containing approximately 30% Humulus
lupulus (hops) extracts (which have been discontinued)
were used to treat gynecological disorders.49,82 However,
early studies to confirm this activity experimentally were
inconclusive or contradictory because of inadequate sensitivity
of the methods used.80,83
More recently, 8-PN has been shown to be the source ofthe
estrogenic activity of Humulus lupulus (hops). 8-PN mimics
the action of17β-estradiol, albeit with less (10- to 20,000-fold)
potency.84-88 It is a potent ligand for the α-estrogen receptor
(ER) with an IC50 value in the nanomolar range; it stimulates
the production of alkaline phosphatase in Ishikawa cells, and
stimulates the growth of estrogen-dependent MCF7 breast
cancer cells.44,89 It was reported that 8-PN has a greater affinity
for the ERα (where it is 70-fold less potent than estradiol)
than for ERβ (reported to be 20,000-fold less potent
than estradiol).90
In a screening for drugs derived from plants for estrogenic
activity, an ethanolic Humulus lupulus (hops) extract (50%;
.2 g/mL) exhibited binding to ERs in intact, estrogendependent
[ER(+)], human breast cancer MCF-7 cells with
a potency equivalent to .5 μg of estradiol per 2 g of dried
Humulus lupulus (hops) strobile (for comparison, the potencies
of 2 g of thyme or red clover were equivalent to .5 or
3 μg of estradiol, respectively).91 Humulus lupulus (hops)
extract also showed significant ability to stimulate cell proliferation
in ER (+) T47D, but not in ER() MDA 468, breast
cancer cells.91 In contrast, in a different series ofexperiments,
a similarly prepared Humulus lupulus (hops) extract at concentrations
of .01-1.0% v/v was found to inhibit serumstimulated
growth of ER(+)T47D breast cancer cells.92
Ovarian cells isolated from immature female rats, which
48 h previously had been injected (primed) with pregnant
mare's serum gonadotropin, were incubated with folliclestimulating
hormone to induce estradiol secretion. The

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