http://groups.yahoo.com/group/aspartameNM/message/917
HERP ranking of carcinogens (formaldehyde is very high):
www.berkeley.edu: Murray 12.14.2 rmforall

[ Comments by Rich Murray are in square brackets. I omitted most of the
listings below .0003, and the 160 references. In this introduction I
quote a few paragraphs from the full review, given below. The HERP
index is a crude, but practical, ranking of substances according to the
actual human cancer risk from the average lifetime exposures to the
levels usually encountered, using data from rats and mice. It does not
accomodate data about extremely heavy individual exposures, about
dangers to farmers, hazards to the environment, any increased toxicity
from simultaneous exposures, unusual individual vulnerability or
sensitivity, or other problems, such as birth defects, reduced quantity
and quality of sperm, subtle interference with human hormones, and
neutrotoxicity.

It is important to note that formaldehyde is at the top of the list,
three times, at daily inhalation intake levels 0.698 mg for ordinary
household air, 2.2 mg for mobile home air, and 6.8 mg industrial
exposure. A heavy user of aspartame will accumulate about 12 mg daily:

http://groups.yahoo.com/group/aspartameNM/message/910
formaldehyde & formic acid from methanol in aspartame:
Murray: 12.9.2 rmforall

It is certain that high levels of aspartame use, above 2 liters daily
for months and years, must lead to chronic formaldehyde-formic acid
toxicity, since 11% of aspartame (1,120 mg in 2L diet soda, 5.6 12-oz
cans) is 123 mg methanol (wood alcohol), immediately released into the
body after drinking (unlike the large levels of methanol locked up in
molecules inside many fruits), then quickly transformed into
formaldehyde, which in turn becomes formic acid, both of which in
time become carbon dioxide and water-- however, about 30% of the
methanol remains in the body as cumulative durable toxic metabolites of
formaldehyde and formic acid-- 37 mg daily, a gram every month.
If 10% of the methanol is retained as formaldehyde, that would give 12
mg daily formaldehyde accumulation, about 60 times more than the 0.2 mg
from 10% retention of the 2 mg EPA daily limit for formaldehyde in
drinking water.

Bear in mind that the EPA limit for formaldehyde in
drinking water is 1 ppm,
or 2 mg daily for a typical daily consumption of 2 L of water.

http://groups.yahoo.com/group/aspartameNM/message/835
RTM: ATSDR: EPA limit 1 ppm formaldehyde in drinking water July 1999
5.30.2 rmforall

This long-term low-level chronic toxic exposure leads to typical
patterns of increasingly severe complex symptoms, starting with
headache, fatigue, joint pain, irritability, memory loss, and leading to
vision and eye problems and even seizures. In many cases there is
addiction. Probably there are immune system disorders, with a
hypersensitivity to these toxins and other chemicals.

Confirming evidence and a general theory are given by Pall (2002):
http://groups.yahoo.com/group/aspartameNM/message/909
testable theory of MCS type diseases, vicious cycle of nitric oxide &
peroxynitrite: MSG: formaldehyde-methanol-aspartame:
Martin L. Pall: Murray: 12.9.2 rmforall ]

http://potency.berkeley.edu/herp.html
HERP Index (Human Exposure/Rodent Potency)

One reasonable strategy is to use a rough index to compare and rank
possible carcinogenic hazards from a wide variety of
chemical exposures at levels that humans typically receive, and then to
focus on those that rank highest (75-77).
Ranking is a critical first step that can help to set priorities for
selecting chemicals for chronic bioassay or mechanistic studies, for
epidemiological research, and for regulatory policy.
Although one cannot say whether the ranked chemical exposures are likely
to be of major or minor importance in human cancer, it is not prudent to
focus attention on the possible hazards at the bottom of a ranking if,
using the same methodology to identify hazard, there are numerous common
human exposures with much greater possible hazards.

Occupational and Pharmaceutical Exposures to some chemicals have been
high, and most of the single chemical agents or
industrial processes evaluated as human carcinogens have been identified
by high dose exposures in the workplace (157).
The issue of how much human cancer can be attributed to occupational
exposure has been controversial, but a few percent seems a
reasonable estimate (28).

Our analyses are based on the HERP index (Human Exposure/Rodent
Potency), which indicates what percentage of the rodent carcinogenic
potency (TD50 in mg/kg/day) a human receives from a given daily lifetime
exposure (mg/kg/day).
TD50 values in our CPDB span a 10 million-fold range across chemicals
(1). [ TD50 means the Toxic Dose average daily level at which 50% of the
exposed rodents die earlier. For instance, rats are about 20 times more
vulnerable than mice to formaldehyde, so the data for rats is used to
estimate the human risk. There is enough formaldehyde in ordinary homes
to give it a high ranking, and the level in mobile homes is three times
higher-- Pall (1990) studied many cases in which mobile home residents
developed MCS-type diseases. ]

In general, the ranking by the simple HERP index is will be similar to a
ranking of regulatory "risk estimates." As we discussed above, the VSD
is approximately equivalent to the ratio of the high dose in a bioassay
divided by 740,000 (14).

Overall, our analyses have shown that HERP values for some historically
high exposures in the workplace and some pharmaceuticals rank high, and
that there is an enormous background of naturally occurring rodent
carcinogens in typical portions of common foods that cast doubt on the
relative importance of low-dose exposures to residues of synthetic
chemicals such as pesticides (75,76,78).
A committee of the National Research Council recently reached similar
conclusions about natural vs. synthetic chemicals in the diet, and
called for further research on natural chemicals (79).

Our earlier HERP rankings were for typical exposures. In this paper we
rank HERP values for average U.S. exposures to rodent carcinogens for
which both concentration data and average exposure data were available.

The average daily U.S. exposures in the ranking (see the table above)
are ordered by possible carcinogenic hazard (HERP).
Results are reported for average exposures to 25 natural chemicals in
the diet (in italics), and to 28 chemicals for which the
exposure is not natural.
Of these 28 chemicals, 5 occur naturally, but human exposure is
primarily or exclusively from anthropogenic sources, e.g. benzene,
chloroform, formaldehyde, TCDD, and tetrachloroethylene.

...the background HERP of 0.0003% for the average chloroform level in a
liter of U.S. tap water, which is formed as a by-product of
chlorination. [This is a very low lifetime danger of cancer.]
***********************************************************************

http://potency.berkeley.edu/herp.html

HERP Index (Human Exposure/Rodent Potency)

We have ranked possible carcinogenic hazards from a variety of common
human exposures to rodent carcinogens, including naturally occurring
chemicals in the diet.

The ranking uses an index (HERP) that indicates for each exposure, the
percentage of the rodent carcinogenic dose that a person receives. The
higher the HERP value, the higher the human exposure is relative to
the dose that gives tumors to rodents. A full discussion follows the
HERP ranking table.

See below for a detailed description of the table.

Potency of carcinogens:
A number in parentheses indicates a TD50 value not used in HERP
calculation because it is the less sensitive species;
"-" = negative in cancer test. "+" = positive for carcinogenicity in
test(s) not suitable for calculating a TD50.
"." = is not adequately tested for carcinogenicity.
TD50 values shown are averages calculated by taking the harmonic mean of
the TD50s of the positive tests in that species from the Carcinogenic
Potency Database. Results are similar if the lowest TD50 value
(most potent) is used instead. For each test the target site with the
lowest TD50 value has been used. The average TD50 has
been calculated separately for rats and mice, and the more sensitive
species is used for calculating the possible hazard.
The database, with references to the source of the cancer tests, is
complete for tests published through 1990 and for the National
Toxicology Program bioassays through 1993.
We have not indicated the route of exposure or target sites or other
particulars of each test, although these are reported in the database.
Daily human exposure: We have tried to use reasonable daily intakes
to facilitate comparisons. The calculations assume a daily dose for a
lifetime; where drugs are normally taken for only a short
period we have bracketed the HERP value.

Possible hazard: The amount of rodent carcinogen indicated under dose is
divided by 70 kg to give a milligram per kilogram of human exposure, and
this human dose is given as the percentage of the TD50 dose in the
rodent (in milligrams per kilogram) to calculate the Human
Exposure/Rodent Potency index (HERP).

Possible hazard HERP (%) Potency of carcinogen: TD50 (mg/kg)
Daily human exposure
Human dose of rodent carcinogen
Rats Mice
140 EDB: workers (high exposure)(before 1977)
Ethylene dibromide, 150 mg 1.52 (7.45)

17 Clofibrate
Clofibrate, 2 g 169 .

14 Phenobarbital, 1 sleeping pill
Phenobarbital, 60 mg (+) 6.09

6.8 1,3-Butadiene: rubber workers (1978-86)
1,3-Butadiene, 66.0 mg (261) 13.9

6.1 Tetrachloroethylene:
dry cleaners with dry-to-dry units (1980-90)
Tetrachloroethylene, 433 mg 101 (126)

4.0 Formaldehyde: workers
Formaldehyde, 6.1 mg 2.19 (43.9)

2.1 Beer, 257 g
Ethyl alcohol, 13.1 ml 9110 (-)

1.4 Mobile home air (14 hours/day)
Formaldehyde, 2.2 mg 2.19 (43.9)

0.9 Methylene chloride: workers (1940s-80s)
Methylene chloride, 471 mg 724 (918)

0.5 Wine, 28.0 g
Ethyl alcohol, 3.36 ml 9110 (-)

0.4 Conventional home air (14 hours/day)
Formaldehyde, 598 µg 2.19 (43.9)

0.1 Coffee, 13.3 g
Caffeic acid, 23.9 mg 297 (4900)

0.04 Lettuce, 14.9 g
Caffeic acid, 7.90 mg 297 (4900)

0.03 Safrole in spices
Safrole, 1.2 mg (441) 51.3

0.03 Orange juice, 138 g
d-Limonene, 4.28 mg 204 (-)

0.03 Pepper, black, 446 mg
d-Limonene, 3.57 mg 204 (-)

0.02 Mushroom (Agaricus bisporus, 2.55 g)
Mixture of hydrazines, etc.
(whole mushroom) - 20,300

0.02 Apple, 32.0 g
Caffeic acid, 3.40 mg 297 (4900)

0.02 Coffee, 13.3 g
Catechol, 1.33 mg 118 (244)

0.02 Coffee, 13.3 g
Furfural, 2.09 mg (683) 197

0.009 BHA: daily US avg (1975)
BHA, 4.6 mg 745 (5530)

0.008 Beer (before 1979), 257 g
Dimethylnitrosamine, 726 ng 0.124 (0.189)

0.008 Aflatoxin: daily US avg (1984-89)
Aflatoxin, 18 ng 0.0032 (+)

0.007 Cinnamon, 21.9 mg
Coumarin, 65.0 µg 13.9 (103)

0.006 Coffee, 13.3 g
Hydroquinone, 333 µg 82.8 (225)

0.005 Saccharin: daily US avg (1977)
Saccharin, 7 mg 2140 (-)

0.005 Carrot, 12.1 g
Aniline, 624 µg 194* (-)

0.004 Potato, 54.9 g
Caffeic acid, 867 µg 297 (4900)

0.004 Celery, 7.95 g
Caffeic acid, 858 µg 297 (4900)

0.004 White bread, 67.6 g
Furfural, 500 µg (683) 197

0.003 Nutmeg, 27.4 mg
d-Limonene, 466 µg 204 (-)

0.003 Conventional home air (14 hour/day)
Benzene, 155 µg (169) 77.5

0.002 Carrot, 12.1 g
Caffeic acid, 374 µg 297 (4900)

0.002 Ethylene thiourea: daily US avg (1990)
Ethylene thiourea, 9.51 µg 7.9 (23.5)

0.002 [DDT: daily US avg (before 1972 ban)]
[DDT, 13.8 µg] (84.7) 12.3

0.001 Plum, 2.00 g
Caffeic acid, 276 µg 297 (4900)

0.001 BHA: daily US avg (1987)
BHA, 700 µg 745 (5530)

0.001 Pear, 3.29 g
Caffeic acid, 240 µg 297 (4900)

0.001 [UDMH: daily US avg (1988)]
[UDMH, 2.82 µg (from Alar)] (-) 3.96

0.0009 Brown mustard, 68.4 mg
Allyl isothiocyanate, 62.9 µg 96 (-)

0.0008 [DDE: daily US avg (before 1972 ban)]
[DDE, 6.91 µg] (-) 12.5

0.0007 TCDD: daily US avg (1994)
TCDD, 12.0 pg 0.0000235 (0.000156)

0.0007 Bacon, 11.5 g
Diethylnitrosamine, 11.5 ng 0.0237 (+)

0.0006 Mushroom (Agaricus bisporus 2.55 g)
Glutamyl-p-hydrazino-benzoate, 107 µg . 277

0.0004 Bacon, 11.5 g
N-Nitrosopyrrolidine, 196 ng (0.799) 0.679

0.0004 Bacon, 11.5 g
Dimethylnitrosamine, 34.5 ng 0.124 (0.189)

0.0004 [EDB: Daily US avg (before 1984 ban)]
[EDB, 420 ng] 1.52 (7.45)

0.0004 Tap water, 1 liter (1987-92)
Bromodichloromethane, 13 µg (72.5) 47.7

0.0003 Mango, 1.22 g
d-Limonene, 48.8 µg 204 (-)

0.0003 Beer, 257 g
Furfural, 39.9 µg (683) 197

0.0003 Tap water, 1 liter (1987-92)
Chloroform, 17 µg (262) 90.3

0.00008 PCBs: daily US avg (1984-86)
PCBs, 98 ng 1.74 (9.58)

0.00008 DDE/DDT: daily US avg (1990)
DDE, 659 ng (-) 12.5

Footnotes:

The following description of the HERP table is excerpted from:
Gold, L. S., Slone, T. H., and Ames, B. N. Overview of analyses of the
Carcinogenic Potency Database. In: Handbook of Carcinogenic Potency and
Genotoxicity Databases (L. S. Gold & E. Zeiger, eds.), Boca Raton, FL:
CRC Press (1997, in press).

Human exposures to natural and synthetic chemicals.

Current regulatory policy to reduce cancer risk, is based on the idea
that chemicals which induce tumors in rodent cancer tests
are potential human carcinogens;
however, the chemicals tested for carcinogenicity in rodents have been
primarily synthetic (1-7).
The enormous background of human exposures to natural chemicals has not
been systematically examined.
This has led to an imbalance in both data and perception about possible
carcinogenic hazards to humans from chemical exposures.
The regulatory process does not take into account:
1) that natural chemicals make up the vast bulk of chemicals humans are
exposed to;
2) that the toxicology of synthetic and natural toxins is not
fundamentally different;
3) that about half of the chemicals tested, whether natural or
synthetic, are carcinogens when tested using current experimental
protocols;
4) that testing for carcinogenicity at near-toxic doses in rodents does
not provide enough information to predict the excess number of human
cancers that might occur at low-dose exposures;
5) that testing at the maximum tolerated dose (MTD) frequently can cause
chronic cell killing and consequent cell replacement (a risk factor for
cancer that can be limited to high doses), and that ignoring
this effect in risk assessment greatly exaggerates risks.

The vast proportion of chemicals to which humans are exposed are
naturally-occurring.
Yet public perceptions tend to identify
chemicals as being only synthetic and only synthetic chemicals as being
toxic; however, every natural chemical is also toxic at some dose.
We estimate that the daily average American exposure to burnt material
in the diet is about 2000 mg, and to natural pesticides (the chemicals
that plants produce to defend themselves against fungi, insects, and
animal predators) about 1500 mg (58).
In comparison, the total daily exposure to all synthetic pesticide
residues combined is about 0.09 mg based on the sum of residues reported
by the U.S. Food and Drug Administration (FDA) in their study of the 200
synthetic pesticide residues thought to be of greatest concern (59).
We estimate that humans ingest roughly 5,000 to 10,000 different natural
pesticides and their breakdown products (58).
Despite this enormously greater exposure to natural chemicals, among the
chemicals tested for carcinogenicity, 78% (1007/1298) are synthetic
(i.e. do not occur naturally).

It has often been assumed that humans have evolved defenses against
natural chemicals that will not protect against synthetic
chemicals. However, humans, like other animals, are extremely well
protected by defenses that are mostly general rather than
specific for particular chemicals (e.g. continuous shedding of surface
cells that are exposed) (58). Additionally, most defense
enzymes are inducible, and are effective against both natural and
synthetic chemicals including potentially mutagenic reactive
chemicals (60).

Since the toxicology of natural and synthetic chemicals is similar, one
expects and finds a similar 50% positivity-rate for
carcinogenicity among synthetic and natural chemicals (see Table 5 in
Gold et al., 1997).

Therefore, since humans are exposed to so many more natural than
synthetic chemicals (by weight and by number), human exposures to
natural rodent carcinogens as defined by high-dose tests are probably
ubiquitous and unavoidable (58,61).

Concentrations of natural pesticides in plants are usually measured in
parts per thousand or million rather than parts per billion, which is
the usual concentration of synthetic pesticide residues or water
pollutants.

A diet free of chemicals that induce tumors in high-dose animal cancer
tests is impossible.

Even though only a tiny proportion of natural pesticides have been
tested for carcinogenicity, 35 of 64 that have been tested are
rodent carcinogens (see Table 5 in Gold et al., 1997), and commonly
occur in plant foods and spices (58,60,62).

Humans also ingest large numbers of natural chemicals from cooking food.
For example, more than 1000 chemicals have been
identified in roasted coffee. Only 26 have been tested for
carcinogenicity according to the most recent results in our CPDB, and
19 of these are positive in at least one test (see Table 12 in Gold et
al., 1997) totaling at least 10 mg of rodent carcinogens per cup
(63-66).
Among the rodent carcinogens in coffee are the plant pesticides caffeic
acid (present at 1800 ppm) (63) and catechol (present at 100 ppm)
(67,68). Two other plant pesticides, chlorogenic acid and neochlorogenic
acid (present at 21,600 ppm and 11,600 ppm respectively) (63) are
metabolized to caffeic acid and catechol but have not been tested for
carcinogenicity. Chlorogenic acid and caffeic acid are mutagenic (69-71)
and clastogenic (72,73). Some other rodent carcinogens in coffee are
products of cooking, e.g. furfural and benzo(a)pyrene. The point here is
not to indicate that rodent data necessarily implicate coffee as a risk
factor for human cancer, but rather to illustrate that there is an
enormous background of chemicals in the diet that are natural and that
have not been a focus of attention for carcinogenicity testing.

The HERP ranking of possible carcinogenic hazards.

Above we discussed that rodent bioassays provide little information
about mechanisms of carcinogenesis and low-dose risk.
Additionally, there is an imbalance in bioassay data because the vast
proportion of test agents are synthetic chemicals while the
vast proportion of human exposures are to naturally occurring chemicals.
Moreover, potency estimates based on bioassay results are bounded by the
doses administered, therefore regulatory risk estimates based on linear
extrapolation are also bounded.
Given these results, what is the best use that can be made of bioassay
data in efforts to prevent human cancer?
In several papers we have emphasized that gaining a broad perspective
about the vast number of chemicals to which humans are exposed can be
helpful when setting research and regulatory priorities (60,74-76).

One reasonable strategy is to use a rough index to compare and rank
possible carcinogenic hazards from a wide variety of
chemical exposures at levels that humans typically receive, and then to
focus on those that rank highest (75-77).
Ranking is a critical first step that can help to set priorities for
selecting chemicals for chronic bioassay or mechanistic studies, for
epidemiological research, and for regulatory policy.
Although one cannot say whether the ranked chemical exposures are likely
to be of major or minor importance in human cancer, it is not prudent to
focus attention on the possible hazards at the bottom of a ranking if,
using the same methodology to identify hazard, there are numerous common
human exposures with much greater possible hazards.
Our analyses are based on the HERP index (Human Exposure/Rodent
Potency), which indicates what percentage of the rodent carcinogenic
potency (TD50 in mg/kg/day) a human receives from a given daily lifetime
exposure (mg/kg/day). TD50 values in our CPDB span a 10 million-fold
range across chemicals (1).

In general, the ranking by the simple HERP index is will be similar to a
ranking of regulatory "risk estimates." As we discussed above, the VSD
is approximately equivalent to the ratio of the high dose in a bioassay
divided by 740,000 (14).

Overall, our analyses have shown that HERP values for some historically
high exposures in the workplace and some pharmaceuticals rank high, and
that there is an enormous background of naturally occurring rodent
carcinogens in typical portions of common foods that cast doubt on the
relative importance of low-dose exposures to residues of synthetic
chemicals such as pesticides (75,76,78).
A committee of the National Research Council recently reached similar
conclusions about natural vs. synthetic chemicals in the diet, and
called for further research on natural chemicals (79).

Our earlier HERP rankings were for typical exposures. In this paper we
rank HERP values for average U.S. exposures to rodent carcinogens for
which both concentration data and average exposure data were available.

The average daily U.S. exposures in the ranking (see the table above)
are ordered by possible carcinogenic hazard (HERP).
Results are reported for average exposures to 25 natural chemicals in
the diet (in italics), and to 28 chemicals for which the
exposure is not natural.
Of these 28 chemicals, 5 occur naturally, but human exposure is
primarily or exclusively from anthropogenic sources, e.g. benzene,
chloroform, formaldehyde, TCDD, and tetrachloroethylene.

Three convenient reference points in the HERP ranking are:
The median HERP value in the above table of 0.001%;
the upper bound risk estimate used by regulatory agencies of one in a
million (using the q1* potency value derived from the linearized
multistage model), i.e. the VSD, which converts to a HERP of 0.00003% if
based on a rat TD50 and 0.00001% if based on a
mouse TD50;
and the background HERP of 0.0003% for the average chloroform level in a
liter of U.S. tap water, which is formed as a by-product of
chlorination.

The HERP ranking maximizes possible hazards to synthetic chemicals
because it includes historically high exposure values that
are now much lower, e.g. DDT, PCBs, occupational exposures.
Additionally, the values for dietary exposures to synthetic
chemicals are averages in the total diet, whereas for many natural
chemicals the exposures are for individual foods (i.e. the
exposures for which concentration data were available).

The above table indicates that many ordinary foods would not pass the
regulatory criteria used for synthetic chemicals.
For many natural chemicals the HERP values are in the top half of the
table, even though natural chemicals are markedly
under-represented because so few have been tested in rodent bioassays.
We discuss several categories of exposure below and
indicate that mechanistic data are available for some chemicals which
suggest that the chemical would not be expected to be a
cancer hazard at the doses to which humans are exposed; thus their
ranking by HERP would not be relevant.

Natural pesticides, because few have been tested, are markedly
underrepresented in our analysis. Importantly, for each plant
food listed, there are about 50 additional untested natural pesticides.

Although ~10,000 natural pesticides and their
break-down products occur in the human diet (58), only 64 have been
tested adequately in rodent bioassays (see Table 5 in
Gold et al., 1997).
Average exposures to many natural-pesticide rodent carcinogens in common
foods rank above or close to the median, ranging up to a HERP of 0.1%.
These include caffeic acid (lettuce, apple, pear, coffee, plum, celery,
carrot, potato); safrole (in spices), allyl isothiocyanate (mustard),
d-limonene (mango, orange juice, black pepper); estragole (in
spices); hydroquinone and catechol in coffee; and coumarin in cinnamon.

Some natural pesticides in the commonly eaten
mushroom (Agaricus bisporus) are rodent carcinogens
(glutamyl-p-hydrazinobenzoate, p-hydrazinobenzoate), and the HERP
based on feeding whole mushrooms to mice is 0.02%.

For d-limonene, no human risk is anticipated because tumors are
induced only in male rat kidney tubules with involvement of
(alpha2u-globulin nephrotoxicity, which does not appear to be
possible in humans (135,136).

Synthetic pesticides currently in use that are rodent carcinogens and
quantitatively detected by the U.S. FDA as residues in
food, are all included in the table above.
Most are at the bottom of the ranking, but HERP values are about at the
median for ethylene thiourea (ETU), UDMH (from Alar) before its
discontinuance, and DDT before its ban in the U.S. in 1972.
These rank below the HERP values for many naturally occurring chemicals.
For ETU the value would be about 10 times lower if the
potency value of the Environmental Protection Agency (EPA) were used
instead of our TD50; EPA combined rodent results
from more than one experiment, including one in which ETU was
administered in utero, and obtained a lower potency (137).
DDT and similar, early pesticides, have been a concern because of their
unusual lipophilicity and persistence, although there is
no convincing epidemiological evidence of a carcinogenic hazard to
humans (138). Current exposure to DDT is in foods of
animal origin, and the HERP value is low, 0.00008%.

In 1984 the U.S. EPA banned the agricultural use of ethylene dibromide
(EDB) the main fumigant in the U.S., because of the residue levels found
in grain, HERP = 0.0004%. This HERP value ranks low, whereas the HERP of
140% for the high exposures to EDB that some workers received in the
1970s is at the top of the ranking (75).

Three synthetic pesticides, captan, chlorothalonil, and folpet, were
evaluated in 1987 by the National Research Council (NRC)
as being of relatively high risk to humans (139), and were also reported
by FDA in the Total Diet Study (TDS).
The contrast between the low ranking HERP values for these pesticides,
ie. the lowest HERP values in Table 9, and the high risk estimates
of the 1987 NRC report is due to exposure estimates, which differ by
more than 100,000-fold.
The NRC used the EPA Theoretical Maximum Residue Contribution, which is
a hypothetical maximum exposure estimate, whereas the FDA used
dietary intake estimates based on monitoring food as eaten. Hence, using
hypothetical maxima, results in enormously higher risk estimates than
using measured residues.

Cooking and preparation of food can also produce chemicals that are
rodent carcinogens.

Alcoholic beverages are a human carcinogen, and the HERP values in the
table above for alcohol in beer (2.1%) and wine (0.5%) are high in the
ranking.

Ethyl alcohol is one of the least potent rodent carcinogens in the CPDB,
but the HERP is high because of high concentrations and high U.S.
consumption. Another fermentation product, urethane (ethyl
carbamate), has a HERP value of 0.00001% in average
beer consumption; for average bread consumption (as toast), the HERP
would be 0.00007%.

Cooking food is plausible as a contributor to cancer. A wide variety of
chemicals are formed during cooking. Rodent
carcinogens formed include furfural and similar furans, nitrosamines,
polycyclic hydrocarbons, and heterocyclic amines.
Furfural, a chemical formed naturally when sugars are heated, is a
widespread constituent of food flavor. The HERP value for
furfural in average consumption of coffee is 0.02% and in white bread is
0.004%. Nitrosamines formed from nitrite or nitrogen
oxides (NOx) and amines in food can give moderate HERP values, e.g. in
bacon, the HERP for diethylnitrosamine is 0.0007%
and for dimethylnitrosamine it is 0.0004%.

A variety of mutagenic and carcinogenic heterocyclic amines (HA) are
formed when meat, chicken or fish are cooked, particularly when charred.
Compared to other rodent carcinogens, there is strong evidence of
carcinogenicity for HAs in terms of positivity rates and multiplicity of
target sites; however, concordance in target sites between
rats and mice is generally restricted to the liver (77). Under usual
cooking conditions, exposures to HA are in the low ppb
range. HERP values for HA in pan fried hamburger range from 0.00006% for
PhIP to 0.000005% for IQ (see the table above). PhIP induces colon
tumors in male but not female rats.

A recent study indicates that whereas the level of DNA adducts in the
colonic mucosa was the same in both sexes, cell proliferation was
increased only in the male, contributing to the formation of
premalignant lesions of the colon (140). Therefore, there was no
correlation between adduct formation and premalignant lesions, but there
was between cell division and lesions.

Food additives can be either naturally occurring rodent carcinogens
(e.g. allyl isothiocyanate and alcohol) or synthetic rodent
carcinogens (butylated hydroxyanisole [BHA] and saccharin, see the table
above). The highest HERP values for average
exposures to synthetic rodent carcinogens in the table above are for
exposures in the 1970s to BHA (0.009%) and saccharin
(0.005%), both nongenotoxic rodent carcinogens. For both of these
additives, data on mechanism of carcinogenesis strongly
suggest that there would be no risk to humans at the levels found in
food.

BHA is a phenolic antioxidant that is Generally Regarded as Safe (GRAS)
by the U.S. FDA. By 1987, after BHA was shown
to be a rodent carcinogen, its use declined six fold (HERP=0.001%)
(100); this was due to voluntary replacement by other
antioxidants, and to the fact that the use of animal fats and oils, in
which BHA is primarily used as an antioxidant, has
consistently declined in the U.S. The mechanistic and carcinogenicity
results on BHA indicate that malignant tumors were
induced only at a dose above the MTD at which cell division is increased
in the forestomach, which is the only site of
tumorigenesis; the proliferation is only at high doses, and is dependent
on continuous dosing until late in the experiment (141).
Humans do not have a forestomach. We note that the dose-response for BHA
curves sharply upward, but the potency value
used in HERP is based on a linear model; if the California EPA potency
value (which is based on a linearized multistage model)
were used in HERP instead of TD50, the HERP values for BHA would be 25
times lower (142).

For saccharin, which has largely been replaced by other sweeteners,
there is convincing evidence that the induced bladder
tumors in rats are not relevant to human dietary exposures. The
carcinogenic effect requires high doses of sodium saccharin
which form calculi in the bladder, and subsequent regenerative
hyperplasia. Thus tumor development is due to increased cell
division, and if the dose is not high enough to produce calculi then
there is no increased cell division and no increased risk of
tumor development (143).

Mycotoxins. Of the 23 fungal toxins tested for carcinogenicity, 14 are
positive (61%) (see Table 5 in Gold et al., 1997). The
mutagenic mold toxin, aflatoxin, which is found in moldy peanut and corn
products, interacts with chronic hepatitis infection in
human liver cancer development (144). There is a synergistic effect in
the human liver between aflatoxin (genotoxic effect) and
the hepatitis B virus (cell division effect) in the induction of liver
cancer (145). The HERP value for aflatoxin of 0.008% is based
on the rodent potency. If the lower human potency value calculated by
U.S. FDA from epidemiological data were used instead,
the HERP would be about 10-fold lower (146). Biomarker measurements of
aflatoxin on populations in Africa and China,
which have high rates of both hepatitis B and C viruses and liver
cancer, confirm that those populations are chronically exposed
to high levels of aflatoxin (147,148). Liver cancer is rare in the U.S.
Although hepatitis B and C viruses infect less than 1 percent of the
U.S. population, hepatitis viruses can account for half of liver cancer
cases among non-Asians and even more among Asians (149).

Ochratoxin A, a rodent carcinogen, has been measured in Europe and
Canada in agricultural and meat products. An estimated
exposure of 1 ng/kg/day would have a HERP value at the median of the
table above (150,151).

Synthetic contaminants. Polychlorinated biphenyls (PCBs) and
tetrachlorodibenzo-p-dioxin (TCDD), which have been a
concern because of their environmental persistence and carcinogenic
potency in rodents, are primarily consumed in foods of
animal origin. In the U.S. PCBs are no longer used, but exposure
persists. Consumption in food in the U.S. declined about
20-fold between 1978-1986 (126,152). The HERP value for the most recent
reporting of the U.S. FDA Total Diet Study (1984-86) is 0.00008%,
towards the bottom of the ranking, and far below
many values for naturally occurring chemicals in
common foods. It has been reported that some countries may have higher
intakes of PCBs than in the U.S. (153).

TCDD, the most potent rodent carcinogen, is produced naturally by
burning when chloride ion is present, e.g. in forest fires.
The sources of human exposure appear to be predominantly anthropogenic,
e.g. from incinerators (154). TCDD has received
enormous scientific and regulatory attention, most recently in an
ongoing assessment by the U.S. EPA (116,154,155). Some
epidemiologic studies suggest an association with human cancer, but the
evidence is not sufficient to establish causality.
Estimation of average U.S. consumption is based on limited sampling
data, and EPA is currently conducting further studies of
concentrations in food. The HERP value of 0.0007% is near the median of
the values in the table above. TCDD exerts many or
all of its harmful effects in mammalian cells through binding to the Ah
receptor. A wide variety of natural substances also bind to
the Ah receptor, (e.g. tryptophan oxidation products) and insofar as
they have been examined, they have similar properties to
TCDD (60). For example, a variety of flavones and other plant substances
in the diet, and their metabolites also bind to the Ah
receptor, e.g. indole carbinol (IC). IC is the main breakdown compound
of glucobrassicin, a glucosinolate that is present in
large amounts in vegetables of the Brassica genus, including broccoli,
and gives rise to the potent Ah binder, indole carbazole (156).

Occupational and Pharmaceutical Exposures to some chemicals have been
high, and most of the single chemical agents or
industrial processes evaluated as human carcinogens have been identified
by high dose exposures in the workplace (157). The
issue of how much human cancer can be attributed to occupational
exposure has been controversial, but a few percent seems a
reasonable estimate (28).

When exposures are high, comparatively little quantitative extrapolation
is required from high-dose rodent tests to those
occupational exposures. HERP values rank at the top of the table above
for chemical exposures in some occupations for which
average exposure data were available: ethylene dibromide, 1,3-butadiene,
tetrachloroethylene, and formaldehyde.

In another analysis, we used Permitted Exposure Limits (PELs) of the
U.S. Occupational Safety and Health Administration as
surrogates for actual exposures, and compared the permitted daily
dose-rate for workers with the TD50 (PERP index,
Permitted Exposure/Rodent Potency) (78,158). We found that PELs for 9
chemicals were greater than 10% of the rodent carcinogenic dose and for
27 they were between 1% and 10% of the rodent dose.

Some pharmaceuticals are also clustered near the top of the HERP
ranking; we note that half the drugs tested are reported in
the Physicians Desk Reference to be carcinogens in rodent bioassays
(19). Most drugs, however, are used for only short periods, and would
not be comparable to HERP values, which are for lifetime exposures.

Caution is necessary in drawing conclusions from the occurrence in the
diet of natural chemicals that are rodent carcinogens. It
is not argued here that these dietary exposures are necessarily of much
relevance to human cancer.

In fact, epidemiological results indicate that adequate consumption of
fruits and vegetables reduces cancer risk at many sites, and that
protective factors like intake of vitamin C and folic acid are
important, rather than intake of individual rodent carcinogens.

Our analysis does indicate that widespread exposures to
naturally-occurring rodent carcinogens cast doubt on the relevance to
human cancer of low-level exposures to synthetic rodent carcinogens. Our
results call for a re-evaluation of the utility of animal cancer tests
done at the MTD for providing information that is useful in protecting
humans against low level exposures in the diet when a high percentage of
both natural and synthetic chemicals appear to be rodent carcinogens at
the MTD, when the data from rodent bioassays is not adequate to assess
low dose risk, and when the ranking on an index of possible hazards
demonstrates that there is an enormous background of natural chemicals
in the diet that rank high, even though so few have been tested in
rodent bioassays.

Our discussion of the HERP ranking indicates the importance of data on
mechanism of carcinogenesis for each chemical. For
several chemicals, mechanistic data has recently been generated which
indicates that they would not be expected to be a risk to
humans at the levels consumed in food (e.g. saccharin, BHA, chloroform,
d-limonene, discussed above). Recent developments
in science and regulatory policy have also emphasized the importance of
evaluating mechanistic data, rather than relying
exclusively on default, worst-case assessments. The National Research
Council and the EPA have both recently recommended
improvements in the risk assessment process that involve incorporating
consideration of dose to the target tissue, mechanism of action, and
biologically based dose-response models, including a possible threshold
of dose below which effects will not occur (159,160).
[160 references] http://potency.berkeley.edu/cpdb.html
Return to the Carcinogenic Potency Project (CPDB) Home Page:
Last updated: April 20, 1999
Carcinogenic Potency Database
Mail Stop: 946
1 Cyclotron Road
Lawrence Berkeley Laboratory
Berkeley, CA 94720 U.S.A.
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aspartame: methanol, formaldehyde, formic acid toxicity:
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Murray: submit complaints and papers to FDA Docket 02P-0317
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http://www.dorway.com/tldaddic.html 5-page review
Roberts HJ Aspartame (NutraSweet) addiction.
Townsend Letter 2000 Jan; HJRobertsMD@...
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