Background: Evidence relating heterocyclic aromatic amines (HCA), associated with high-temperature cooking methods, to prostate cancer risk is inconsistent.

Methods: In a large U.S. cohort study, intakes of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), and 2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline (DiMeIQx) and a meat-derived mutagenicity (MDM) index were assessed using a cooking method questionnaire administered in 1996. Until 2010, 2,770 prostate cancer cases were observed among 26,030 participants.

Results: Intake of PhIP from red meat was statistically significantly associated with total prostate cancer risk (top vs. bottom quintile HR, 1.18; 95% confidence intervals; CI, 1.03–1.35), but not other HCAs (MeIQx, 1.12; 0.98–1.27, PhIP from white meat, 1.08; 0.95–1.22, DiMeIQx, 1.09; 0.97–1.21) or MDM (1.13; 1.00–1.28). For high-grade (Gleason sum 7 with pattern 4+3 and Gleason sum 8–10, n = 483 cases) and advanced cancers (n = 281), we only observed positive associations for PhIP from red meat (top vs. bottom quintile: high grade: HR, 1.44; 95% CI, 1.04–1.98, Ptrend = 0.03; advanced: HR, 1.50; 95% CI, 0.99–2.26; Ptrend = 0.12), but associations for advanced cancers did not reach statistical significance. Observed associations remained similar after adjustment for total, unprocessed, or processed red meat intake.

Conclusion: Observed positive associations between PhIP intake from red meat and prostate cancer, particularly high-grade and possibly also advanced prostate cancer, need to be confirmed in other studies.

Impact: Results do not provide strong evidence that HCAs increase risk of prostate cancers. Cancer Epidemiol Biomarkers Prev; 24(10); 1557–63. ©2015 AACR.

Higher meat, especially red meat consumption has been suggested to be associated with higher risk of prostate cancer, but the evidence is not consistent (reviewed in ref. 1). One possible mechanism through which red meat may be involved in prostate carcinogenesis is the formation of mutagenic heterocyclic amines (HCA) in muscle meat when meats are cooked at high temperature and for long duration (e.g., grilling, barbecuing, frying, and broiling; ref. 2).

HCAs were first detected in the 1970s in smoke condensate of grilled fish and were shown to be mutagenic (3). HCAs are formed from precursors (creatine/creatinine, sugar, amino acids) found in the muscle of meat and fish cooked at temperatures exceeding 130°C (4, 5). HCA production and amount depend mainly on cooking method, temperature, and the type of meat or fish (4). Meat drippings and gravy made from these drippings contain considerable amounts of HCA (6). The most abundant HCAs in the human diet are 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) and 2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline (DiMeIQx; ref. 7).

Thus far, five cohort studies have examined the association between HCA intake and prostate cancer risk. Some reported positive associations for red meat that was consumed mostly well done (8–10) or for HCA intake (10), in particular with advanced disease. Two found no associations (11, 12). In addition, three (13–15) of five (16, 17) case–control studies reported no clear associations between HCA intake and risk of prostate cancer.

The aim of this study was to examine in the PSA era the association of HCA intake and a meat-derived mutagenicity (MDM) index with risk of prostate cancer in a large prospective U.S. cohort study.

Study population

The Health Professionals Follow-up Study includes 51,529 dentists, veterinarians, pharmacists, optometrists, osteopathic physicians, and podiatrists who were between 40 and 75 years of age at enrollment in 1986. At baseline, all participants completed a 131-item semi-quantitative food-frequency questionnaire (FFQ) and provided information on age, race or ethnicity, weight, height, physical activity, cigarette smoking, alcohol consumption, and medical history. Every 2 years, questionnaires were mailed to collect updated information on exposure and new diagnoses; follow-up FFQs were mailed every 4 years. The validity and reproducibility of our FFQs have been documented previously (18). Deaths were reported by next-of-kin, the postal service, and searches of the National Death Index. The study was approved by the Human Subjects Committee at the Harvard School of Public Health (Boston, MA).

In 1996, questions on meat preparation (cooking method and degree of doneness) were included on the biennial questionnaire. This analysis is based on the cohort of men who provided information on meat preparation in 1996 and who responded to the 1994 FFQ. Of these participants, we excluded all men with a cancer diagnosis except for nonmelanoma skin cancer before 1996 and men with missing information on meat preparation (no answer to any of the cooking method questions, missing frequency of meat intake of at least one cooked meat item, or no information on bacon consumption, which is needed to estimate HCA intake). The final cohort for this analysis included 26,030 men.

Case ascertainment

On the biennial follow-up questionnaires, men were asked to report whether they were diagnosed with prostate cancer, in the previous 2 years. Diagnosis was confirmed by review of medical records (>90% of the cases). For nonresponders, we used information from the National Death Index, postal service, and next-of-kin to determine whether a participant had died. After the review of death certificates, informed consent was obtained from next-of-kin of participants who died of prostate cancer to obtain medical records. Study investigators reviewed the medical records to confirm a prostate cancer diagnosis and prostate cancer deaths.

This analysis was based on 2,770 non-T1a prostate cancer cases ascertained after the date of return of the 1996 questionnaire through January 31, 2010. Of these cancer cases, 281 were classified as advanced or lethal [diagnosed at an advanced stage (T3b, T4, N1, and M1), developed metastases during follow-up, or died due to prostate cancer]. We confirmed 2,285 cases as organ-confined or having limited extraprostatic extension (T1b, T1c, T2, T3a, and N0 or Nx and M0), and the remainder could not be assigned a stage. We defined low-grade prostate cancer as patients having Gleason sum of 2–6 or 7 with a pattern of 3 plus 4 (n = 1859) and high-grade cases as those with Gleason sum 7 and pattern of 4 plus 3 and those with Gleason sum 8–10 (n = 483).

Assessment of meat consumption and cooking methods

Total, red (processed and unprocessed), and white meat intake was estimated from the 1994 FFQ. For each food item, a commonly used unit or serving size was specified. The participants were asked to indicate how often, on average, they consumed each food item, with nine possible response categories ranging from “never” to “six or more times per day.” In 1996, participants completed a cooking methods questionnaire based on the results of a pilot study, which ascertained a group of cooking method questions that best predicted HCA intake in the HPFS (7). Information on cooking methods and typical outside appearance of pan-fried, broiled, and grilled or barbecued chicken, hamburger, and steak; fried, microwaved, and broiled bacon; fried sausage; roast beef; and homemade gravy were assessed (7). On the basis of the results of the pilot study, variation in doneness level of fried bacon was small. Therefore, fried bacon intake was based on the 1994 FFQ and assumed to be medium browned (7). The Charred Database (19) contains data on HCA and MDM concentration in various meat items depending on cooking method and outside appearance (20). The mutagenic activity of meat samples was assessed by the Ames/Salmonella test. The resulting MDM is a measure of the total mutagenic activity found in cooked meats, which integrates mutagenic activity from all classes of mutagens, including heterocyclic amines, but also benzo[a]pyrene or yet unidentified compounds, found in cooked meats (21).

A participant's HCA intake or MDM was calculated by multiplying the given consumption frequency of each food by its HCA content or MDM value for the specified cooking method and degree of browning derived from the Charred Database (20).

Statistical analysis

Intake of PhIP, MeIQx, DiMeIQx, and MDM index was categorized into quintiles based on the distribution in the analytic cohort. We calculated HRs and corresponding 95% confidence intervals (CI) using Cox proportional hazards regression to evaluate the association of HCA intake and MDM index with total and advanced or lethal prostate cancer. We observed no violation of the proportional hazards assumption. The models were adjusted for age, race/ethnicity, pack-years smoked in the past 10 years, family history of prostate cancer, updated history of diabetes mellitus, height, body mass index (BMI) at age 21, updated vigorous leisure-time physical activity, updated current aspirin use, cumulative average updated intake of tomato products and fish, and updated intake of energy, alcohol, vitamin E, α-linolenic acid, and total calcium. We decided on this set of confounders a priori based on the overall literature. Cumulative updated average intake represents the average intake of a food or nutrient from all available FFQs up to the start of each follow-up interval (22). To test whether associations between HCA intake or MDM index might be explained by meat intake per se, we ran models that additionally adjusted for (i) total red meat, (ii) unprocessed red meat [which includes regular hamburger; lean or extra-lean hamburger; beef, pork, or lamb as a sandwich or mixed dish (e.g., stew, casserole, lasagna, etc.); beef or lamb as a main dish (e.g., steak, roast, ham, etc.); pork as a main dish (e.g., ham or chops)], (iii) processed red meat salami, bologna, or other processed meat sandwiches; other processed meats [e.g., sausage, kielbasa, etc.); bacon; hot dogs], and (d) white meat (chicken and turkey). We also examined the association of total red meat, unprocessed red meat, processed red meat and white meat consumption in 1994 (closest date to HCA assessment in 1996) and the risk of prostate cancer. To test for trend, we entered the median of each quintile of HCA intake or MDM index as a single continuous variable into the model and used the Wald test to assess statistical significance of the coefficient. We ran stratified models to determine whether the associations of HCA intake or MDM index with prostate cancer varied by age (<60 vs. ≥60 years in 1996), current BMI, aspirin use (nonusers in 1996 vs. user; infrequent vs. frequent user; never user vs. user), consumption of tomato products (sum of tomato sauce and pizza; < vs. ≥2.0 servings/week), intake of vitamin E (< vs. ≥ median intake), and history of prostatitis. In a sensitivity analysis, we restricted the analysis to men who have had at least one PSA test until the end of the observation period in 2010. The presence of multiplicative interaction was assessed by including a cross-product term for these factors and HCA intake or MDM index in the regression model along with the main effect terms. The statistical significance of the coefficient for the cross-product term was evaluated by the Wald test. A P value of <0.05 was considered statistically significant.

The analysis included 2,770 prostate cancer cases in 314,746 person-years of follow-up. Selected baseline characteristics of the study participants by highest and lowest category of PhIP, MeIQx, and DiMeIQx intake are shown in Table 1. Participants in the highest categories engaged less often in vigorous physical activity and were more likely to have smoked in the past 10 years. These participants also had a higher intake of red meat, but lower intake of vitamin E than participants in the lowest quintiles.

Intake of PhIP from red meat was statistically significantly associated with total prostate cancer risk (multivariable HR = 1.18; 95% CI, 1.03–1.35, top vs. bottom quintile; Table 2). However, intake of PhIP from white meat or intake of MeIQx, DiMeIQx, or the MDM index was not associated with total prostate cancer risk (Table 2). For high-grade cancers (Gleason sum 7 with pattern 4+3 and Gleason sum 8–10, n = 483 cases), we also observed an increased risk among participants with high intake of PhIP from red meat (HR = 1.44; 95% CI, 1.04–1.98, Ptrend = 0.03), but we did not observe any significant associations with MDM index (HR = 1.05; 95% CI, 0.78–1.41, Ptrend = 0.54), MeIQx, PhIP from white meat, or DiMeIQx.

For advanced cancers (n = 281), we only observed positive associations for PhIP from red meat (top vs. bottom quintile: HR = 1.50 (95% CI, 0.99–2.26; Ptrend = 0.12), but associations for advanced cancers did not reach statistical significance (Table 2). HCA intake or MDM index was not statistically significantly associated with the risk of organ-confined or low-grade prostate cancer (data not shown).

Adding total red meat intake to the multivariable model did not materially change the associations between HCA intake or MDM index with total, advanced, and high-grade prostate (data not shown); results were also similar after adding unprocessed red meat or processed meat separately to the models (data not shown). Similarly, no major changes were observed when adding white meat to the model. In order to evaluate whether the effect on high-grade and advanced tumors was due to HCA or other carcinogens in cooked meat, we included both MDM and PhIP from red meat into the same model; but the risk estimates for PhIP from red meat were similar (top vs. bottom quintile, HR, 95% CI; high grade: PhIP from red meat 1.50, 1.06–2.14; MDM 0.90, 0.65–1.23; advanced: PhIP from red meat 1.45, 0.92–2.28; MDM 1.17, 0.76–1.81).

Generally, the associations of HCA intake or MDM index with total prostate cancer were not modified by age, BMI, aspirin use, vitamin E intake, or history of prostatitis (all Pinteraction > 0.05; data not shown). However, we observed an increased risk of total prostate cancer associated with high HCA intake or MDM index among those with lower (but not higher) consumption of tomato products; however, interactions were not statistically significant, except for MDM (Pinteraction = 0.03; Table 3). Excluding men who had never had a PSA test did not change our results appreciably (data not shown).

In joint analysis, we observed that men with both low tomato consumption and high MDM had a 22% (95% CI, 2%–47%) higher risk of developing prostate cancer when compared with those with high tomato consumption and low MDM (data not shown).

In this large prospective cohort study conducted in the PSA era, we did not observe statistically significant associations between HCA intake and risk of prostate cancer. However, we observed positive associations between PhIP intake from red meat and risk of total, high-grade and advanced prostate cancer. Also, we noted that men with low tomato product consumption had an increased risk of total prostate cancer associated with intake of some HCAs or the MDM index, whereas no increased risks were observed among men with high tomato product consumption.

Heterocyclic amines have consistently been shown to be mutagenic in mutagenicity assays and carcinogenic in animal models (23, 24). PhIP contributes most to HCA intake in the United States, whereas DiMeIQx intake is comparably low, but is the most mutagenic HCA of the three examined HCAs (25). Epidemiologic evidence for an association between HCA intake and prostate cancer, however, is limited. In the most recent study, conducted among participants of the California Collaborative Prostate Cancer Study (16), high consumption of red meat cooked at high temperature and well-done red meat were positively associated with risk of advanced, but not overall prostate cancer. Intake of PhIP was also positively, although not statistically significantly, related with advanced prostate cancer. This result is similar to what has been reported in the NIH–AARP cohort (8). High intake of very well-done meat and of PhIP was associated with an increased risk of prostate cancer in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (10). In the Agricultural Health Study (9), consumption of well or very well-done meat was related to an increased risk of total and in particular advanced prostate cancer, and there were nonstatistically significant positive associations with DiMeIQx and MeIQx intakes. In the Multiethnic cohort (11) and the EPIC–Heidelberg cohort (12), no associations of HCA intake or type of meat cooking or degree of doneness with risk of prostate cancer overall or with advanced disease were observed. In two case–control studies, HCA intake was not clearly associated with prostate cancer risk (13–15), although another study by John and colleagues (13) reported a positive association of well-done and grilled red meat consumption with risk of advanced prostate cancer. A fourth case–control study including 470 cases of aggressive prostate cancer-related high intake of well-done meat and intake of MeIQx and DiMeIQx to an increased risk (17).

It is of interest to note that we observed associations between PhIP intake from red but not from white meat with risk of high-grade prostate cancer, although PhIP intake from white meat is twice as high as the intake from red meat. In addition, associations for PhIP from red meat remained similar after we adjusted for total, unprocessed, and processed meat intake separately. This argues against a causal association between PhIP intake (or HCA intake in general) and prostate cancer risk, and suggest the possibility that not HCA themselves but other mutagenic compounds that arise from cooking of red meat may also be a risk factor for prostate cancer. MDM integrates mutagenic activity of different compounds in cooked meats such as heterocyclic amines or benzo[a]pyrene, but also yet unidentified compounds (21). However, when we examined associations between PhIP from red meat and MDM and high-grade or advanced cancers in the same model estimates for PhIP from red meat were similar to estimates without MDM in the model.

In the rat, PhIP induced mutations in the ventral prostate, which was associated with an infiltrate of inflammatory cells (26). Similarly, PhIP induced prostate cancer in a CYP1A-humanized mice model, which is preceded by inflammatory proliferative epithelial lesions (27). In our analysis, we did not observe evidence for effect modification of the association between HCA intake or MDM index and prostate cancer risk by use of aspirin, intake of dietary vitamin E, or BMI, all of which are factors that influence inflammatory processes. We did, however, observe that associations were modified by consumption of tomato products. Lycopene is a potent antioxidant found in tomatoes (28), but the mechanism by which lycopene may modify the association of HCA intake and prostate cancer is currently unclear. Animal studies did not provide clear evidence that administration of lycopene reduced formation of HCA-DNA adducts, reduced oxidative stress induced by HCA administration, or influenced levels of phase II enzymes (29, 30). However, lycopene may affect cell cycle, apoptosis, inflammation, and angiogenesis by a variety of pathways (31, 32). To the best of our knowledge, this is the first study to observe a modifying effect of tomato intake on risk of prostate cancer and, thus, our results need to be confirmed by other studies. However, we cannot exclude the possibility that our results are due to chance and, thus, warrant confirmation from other studies.

We observed positive associations of PhIP intake from red meat with total, high-grade and advanced prostate cancer; even though associations for advanced cancers did not reach statistical significance. However, the number of advanced or lethal cases in our analytical cohort was small because we began follow-up in 1996 after the completion of the questionnaire, that is, in the PSA era; about 95% of men included in our analysis had reported at least one PSA between 1996 until the end of the follow-up period. Other studies that had reported associations of HCA intake with advanced prostate cancer (9, 13, 16, 17) did not separately evaluate high-grade disease.

We assessed meat cooking habits in 1996 and used that information throughout follow-up. It is possible that participants might have changed their meat preparation habits or overall meat intake during follow-up, which may result in another source of measurement error. For example, red meat consumption decreased in the HPFS over time. In 2004, we assessed meat cooking methods a second time in the HPFS cohort, and correlations between calculated HCA intake in 1996 and 2004 were r = 0.31, 0.40, and 0.23 (all P < 0.0001) for PhIP, MeIQx, and DiMeIQx, respectively. HCA intake estimations suffer from imprecision. Assessing a person's dietary intake by means of a FFQ is prone to recall bias due to over- or underestimation of dietary intake by the study participant leading to misclassification with respect to dietary intake. We estimated HCA intake and MDM index based on participants' responses to questions on the cooking method of specific meat items. Doneness levels specified by participants are proxies of the actual intake of heterocyclic amines, which varies by duration of cooking, temperatures used (33), type of oil used (34, 35), handling of the meat before and during the cooking process (36) as well as of the cooking method itself (37) such that cooking short time by high temperature and long time by lower temperature can result in the same degree of browning but not in the same degree of doneness. In addition, the use of limited data on the HCA content in differently prepared meats for the computation of HCA intake is another major shortcoming of this approach to quantify intake (38). However, the cooking questions used in this study are based on a pilot study (7) that determined which set of questions best predicted HCA intake in our cohorts. Also, because data on cooking methods were obtained before cancer diagnosis, possible measurement errors due to the aforementioned factors should be nondifferential, which tends to attenuate associations.

In conclusion, our results do not provide strong evidence that HCAs in general increase risk of prostate cancers. Observed associations between PhIP intake from red meat and prostate cancer, particularly high-grade and possibly also advanced prostate cancer need to be confirmed in other studies.

No potential conflicts of interest were disclosed.

Conception and design: W.C. Willett, E.A. Platz, K. Wu

Development of methodology: R. Sinha, E.L. Giovannucci

Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.): W.C. Willett, E.L. Giovannucci, E.A. Platz

Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): S. Rohrmann, K. Nimptsch, R. Sinha, W.C. Willett, E.L. Giovannucci, E.A. Platz, K. Wu

Writing, review, and/or revision of the manuscript: S. Rohrmann, K. Nimptsch, R. Sinha, W.C. Willett, E.L. Giovannucci, E.A. Platz, K. Wu

Study supervision: E.L. Giovannucci, E.A. Platz, K. Wu

The authors thank the participants and staff of the Health Professionals Follow-up Study for their valuable contributions as well as the following state cancer registries for their help: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA, WY. The authors assume full responsibility for analyses and interpretation of these data.

This work was supported by NIH grants UM1 CA167552 (to W.C. Willett), P01 CA055075 (to W.C. Willett), and R01 CA133891 (to E.L. Giovannucci).

1.
Alexander
DD
,
Mink
PJ
,
Cushing
CA
,
Sceurman
B
. 
A review and meta-analysis of prospective studies of red and processed meat intake and prostate cancer
.
Nutr J
2010
;
9
:
50
.
2.
Michaud
DS
,
Augustsson
K
,
Rimm
EB
,
Stampfer
MJ
,
Willet
WC
,
Giovannucci
E
. 
A prospective study on intake of animal products and risk of prostate cancer
.
Cancer Causes Control
2001
;
12
:
557
67
.
3.
Sugimura
T
. 
Overview of carcinogenic heterocyclic amines
.
Mutat Res
1997
;
376
:
211
9
.
4.
Skog
KI
,
Johansson
MA
,
Jagerstad
MI
. 
Carcinogenic heterocyclic amines in model systems and cooked foods: a review on formation, occurrence and intake
.
Food Chem Toxicol
1998
;
36
:
879
96
.
5.
Jagerstad
M
,
Skog
K
,
Grivas
S
,
Olsson
K
. 
Formation of heterocyclic amines using model systems
.
Mutat Res
1991
;
259
:
219
33
.
6.
Gross
GA
,
Gruter
A
. 
Quantitation of mutagenic/carcinogenic heterocyclic aromatic amines in food products
.
J Chromatogr
1992
;
592
:
271
8
.
7.
Byrne
C
,
Sinha
R
,
Platz
EA
,
Giovannucci
E
,
Colditz
GA
,
Hunter
DJ
, et al
Predictors of dietary heterocyclic amine intake in three prospective cohorts
.
Cancer Epidemiol Biomarkers Prev
1998
;
7
:
523
9
.
8.
Sinha
R
,
Park
Y
,
Graubard
BI
,
Leitzmann
MF
,
Hollenbeck
A
,
Schatzkin
A
, et al
Meat and meat-related compounds and risk of prostate cancer in a large prospective cohort study in the United States
.
Am J Epidemiol
2009
;
170
:
1165
77
.
9.
Koutros
S
,
Cross
AJ
,
Sandler
DP
,
Hoppin
JA
,
Ma
X
,
Zheng
T
, et al
Meat and meat mutagens and risk of prostate cancer in the Agricultural Health Study
.
Cancer Epidemiol Biomarkers Prev
2008
;
17
:
80
7
.
10.
Cross
AJ
,
Peters
U
,
Kirsh
VA
,
Andriole
GL
,
Reding
D
,
Hayes
RB
, et al
A prospective study of meat and meat mutagens and prostate cancer risk
.
Cancer Res
2005
;
65
:
11779
84
.
11.
Sharma
S
,
Cao
X
,
Wilkens
LR
,
Yamamoto
J
,
Lum-Jones
A
,
Henderson
BE
, et al
Well-done meat consumption, NAT1 and NAT2 acetylator genotypes and prostate cancer risk: the multiethnic cohort study
.
Cancer Epidemiol Biomarkers Prev
2010
;
19
:
1866
70
.
12.
Sander
A
,
Linseisen
J
,
Rohrmann
S
. 
Intake of heterocyclic aromatic amines and the risk of prostate cancer in the EPIC-Heidelberg cohort
.
Cancer Causes Control
2010
;
22
:
109
14
.
13.
John
EM
,
Stern
MC
,
Sinha
R
,
Koo
J
. 
Meat consumption, cooking practices, meat mutagens, and risk of prostate cancer
.
Nutr Cancer
2011
;
63
:
525
37
.
14.
Rovito
PM
 Jr
,
Morse
PD
,
Spinek
K
,
Newman
N
,
Jones
RF
,
Wang
CY
, et al
Heterocyclic amines and genotype of N-acetyltransferases as risk factors for prostate cancer
.
Prostate Cancer Prostatic Dis
2005
;
8
:
69
74
.
15.
Norrish
AE
,
Ferguson
LR
,
Knize
MG
,
Felton
JS
,
Sharpe
SJ
,
Jackson
RT
. 
Heterocyclic amine content of cooked meat and risk of prostate cancer
.
J Natl Cancer Inst
1999
;
91
:
2038
44
.
16.
Joshi
AD
,
Corral
R
,
Catsburg
C
,
Lewinger
JP
,
Koo
J
,
John
EM
, et al
Red meat and poultry, cooking practices, genetic susceptibility and risk of prostate cancer: results from a multiethnic case-control study
.
Carcinogenesis
2012
;
33
:
2108
18
.
17.
Punnen
S
,
Hardin
J
,
Cheng
I
,
Klein
EA
,
Witte
JS
. 
Impact of meat consumption, preparation, and mutagens on aggressive prostate cancer
.
PLoS ONE
2011
;
6
:
e27711
.
18.
Rimm
EB
,
Giovannucci
EL
,
Stampfer
MJ
,
Colditz
GA
,
Litin
LB
,
Willett
WC
. 
Reproducibility and validity of an expanded self-administered semiquantitative food frequency questionnaire among male health professionals
.
Am J Epidemiol
1992
;
135
:
1114
26
.
19.
National Cancer Institute
. 
CHARRED: computerized heterocyclic amines database resource for research in the epidemiologic of disease 2006 [cited 2015 May 7]
;
Available from
: http://dceg.cancer.gov/tools/design/charred
20.
Sinha
R
,
Cross
A
,
Curtin
J
,
Zimmerman
T
,
McNutt
S
,
Risch
A
, et al
Development of a food frequency questionnaire module and databases for compounds in cooked and processed meats
.
Mol Nutr Food Res
2005
;
49
:
648
55
.
21.
Sinha
R
,
Kulldorff
M
,
Chow
WH
,
Denobile
J
,
Rothman
N
. 
Dietary intake of heterocyclic amines, meat-derived mutagenic activity, and risk of colorectal adenomas
.
Cancer Epidemiol Biomarkers Prev
2001
;
10
:
559
62
.
22.
Willett
WC
. 
Nutritional Epidemiology
. Second ed.
New York
:
Oxford University Press
; 
1998
.
23.
Shirai
T
,
Tamano
S
,
Sano
M
,
Masui
T
,
Hasegawa
R
,
Ito
N
. 
Carcinogenicity of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in rats: dose–response studies
.
Princess Takamatsu Symp
1995
;
23
:
232
9
.
24.
Snyderwine
EG
,
Turesky
RJ
,
Turteltaub
KW
,
Davis
CD
,
Sadrieh
N
,
Schut
HA
, et al
Metabolism of food-derived heterocyclic amines in nonhuman primates
.
Mutat Res
1997
;
376
:
203
10
.
25.
Wang
CY
,
Debiec-Rychter
M
,
Schut
HAJ
,
Morse
P
,
Jones
RF
,
Archer
C
, et al
N-Acetyltransferase expression and DNA binding of N-hydroxyheterocyclic amines in human prostate epithelium
.
Carcinogenesis
1999
;
20
:
1591
6
.
26.
Nakai
Y
,
Nelson
WG
,
De Marzo
AM
. 
The dietary charred meat carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine acts as both a tumor Initiator and promoter in the rat ventral prostate
.
Cancer Res
2007
;
67
:
1378
84
.
27.
Li
G
,
Wang
H
,
Liu
AB
,
Cheung
C
,
Reuhl
KR
,
Bosland
MC
, et al
Dietary carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine-induced prostate carcinogenesis in CYP1A-humanized mice
.
Cancer Prev Res
2012
;
5
:
963
72
.
28.
Stahl
W
,
Sies
H
. 
Lycopene: a biologically important carotenoid for humans?
Arch Biochem Biophys
1996
;
336
:
1
9
.
29.
Breinholt
V
,
Lauridsen
ST
,
Daneshvar
B
,
Jakobsen
J
. 
Dose–response effects of lycopene on selected drug-metabolizing and antioxidant enzymes in the rat
.
Cancer Lett
2000
;
154
:
201
10
.
30.
Dingley
KH
,
Ubick
EA
,
Chiarappa-Zucca
ML
,
Nowell
S
,
Abel
S
,
Ebeler
SE
, et al
Effect of dietary constituents with chemopreventive potential on adduct formation of a low dose of the heterocyclic amines PhIP and IQ and phase II hepatic enzymes
.
Nutr Cancer
2003
;
46
:
212
21
.
31.
Trejo-Solis
C
,
Pedraza-Chaverri
J
,
Torres-Ramos
M
,
Jimenez-Farfan
D
,
Cruz Salgado
A
,
Serrano-Garcia
N
, et al
Multiple molecular and cellular mechanisms of action of lycopene in cancer inhibition
.
Evid Based Complement Alternat Med
2013
;
2013
:
705121
.
32.
Holzapfel
NP
,
Holzapfel
BM
,
Champ
S
,
Feldthusen
J
,
Clements
J
,
Hutmacher
DW
. 
The potential role of lycopene for the prevention and therapy of prostate cancer: from molecular mechanisms to clinical evidence
.
Int J Mol Sci
2013
;
14
:
14620
46
.
33.
Skog
K
,
Steineck
G
,
Augustsson
K
,
Jagerstad
M
. 
Effect of cooking temperature on the formation of heterocyclic amines in fried meat products and pan residues
.
Carcinogenesis
1995
;
16
:
861
7
.
34.
Johansson
M
,
Skog
K
,
Jagerstad
M
. 
Effects of edible oils and fatty acids on the formation of mutagenic heterocyclic amines in a model system
.
Carcinogenesis
1993
;
14
:
89
94
.
35.
Persson
E
,
Graziani
G
,
Ferracane
R
,
Fogliano
V
,
Skog
K
. 
Influence of antioxidants in virgin olive oil on the formation of heterocyclic amines in fried beefburgers
.
Food Chem Toxicol
2003
;
41
:
1587
97
.
36.
Salmon
CP
,
Knize
MG
,
Felton
JS
. 
Effects of marinating on heterocyclic amine carcinogen formation in grilled chicken
.
Food Chem Toxicol
1997
;
35
:
433
41
.
37.
Skog
K
. 
Problems associated with the determination of heterocyclic amines in cooked foods and human exposure
.
Food Chem Toxicol
2002
;
40
:
1197
203
.
38.
Rohrmann
S
,
Zoller
D
,
Hermann
S
,
Linseisen
J
. 
Intake of heterocyclic aromatic amines from meat in the EPIC-Heidelberg cohort
.
Br J Nutr
2007
;
98
:
1112
5
.