Hemolymphoreticular Neoplasias from the Ramazzini Institute Long-term Mice and Rat Studies on Aspartame

Federica Gnudi; Simona Panzacchi; Eva Tibaldi; Martina Iuliani; Daria Sgargi; Luciano Bua; Daniele Mandrioli

doi:10.5334/aogh.4163

Hemolymphoreticular Neoplasias from the Ramazzini Institute Long-term Mice and Rat Studies on Aspartame

Volume 89 (2023): Issue 1

By: Federica Gnudi , Simona Panzacchi , Eva Tibaldi , Martina Iuliani , Daria Sgargi , Luciano Bua and Daniele Mandrioli

Open Access

|Jun 2023

Figures & Tables

Table 1

Long-term carcinogenicity bioassay on APM administered ad libitum with feed to Sprague-Dawley rats from 8 weeks of age (BT6008): animals bearing HLRN, lymphoma (all types), histiocytic sarcoma, leukemia (all types).

GROUP	DOSE PPM (mg/kg bw)	ANIMALS		ANIMALS BEARING HLRN^a				LYMPHOMAS (ALL TYPES)^a			HISTIOCYTIC SARCOMA^a			LEUKEMIAS (ALL TYPES)^a
GROUP	DOSE PPM (mg/kg bw)	SEX	NO.	NO.	%			NO.	%		NO.	%		NO.	%
I	100000	M	100	29	29.0			24	24.0	P = 0.016; *P = 0.026	3	3.0		2	2.0
I	(5000)	F	100	25	25.0	○○	P < 0.001; *P = 0.001	14	14.0	P = 0.028; *P = 0.043	7	7.0		4	4.0	P = 0.025; *P = 0.025
II	50000	M	100	20	20.0			13	13.0		6	6.0		1	1.0
II	(2500)	F	100	25	25.0	○○	P < 0.001; *P = 0.001	12	12.0		8	8.0	*P = 0.053	5	5.0	P = 0.010; *P = 0.010
III	10000	M	100	15	15.0			8	8.0		3	3.0		4	4.0
III	(500)	F	100	19	19.0	○	P = 0.015; *P = 0.020	7	7.0		10	10.0	P = 0.015; *P = 0.022	2	2.0
IV	2000	M	150	33	22.0			16	10.7		10	6.7		7	4.7
IV	(100)	F	150	28	18.7	○	P = 0.009; *P = 0.018	14	9.3		8	5.3		6	4.0	P = 0.015; *P = 0.030
V	400	M	150	25	16.7			22	14.7		2	1.3		1	0.7
V	(20)	F	150	30	20.0	○○	P = 0.004; *P = 0.008	17	11.3		9	6.0		5	3.3	*P = 0.030
VI	80	M	150	23	15.3			15	10.0		4	2.7		4	2.7
VI	(4)	F	150	22	14.7			14	9.3		6	4.0		2	1.3
VII	0	M	150	31	20.7	◊ ○	#P = 0.0173	19	12.7	#P = 0.0016	8	5.3		4	2.7
VII	0	F	150	13	8.7	◊◊ ○	#P = 0.0048	9	6.0		4	2.7		0	0.0

[i] ^a Percentages refer to the number of animals at start.

Previous statistical analyses (Soffritti et al., 2006).

◊ Statistically significant (p ≤ 0.05) using Cochran-Armitage test.

◊◊ Statistically significant (p ≤ 0.01) using Cochran-Armitage test.

○ Statistically significant (p ≤ 0.05) using poly-k test (k = 3).

○○ Statistically significant (p ≤ 0.01) using poly-k test (k = 3).

New statistical analyses (in bold):

* One-tailed Fisher’s exact test; ** Two-tailed Fisher’s exact test.

# Cochran–Armitage test for trend.

Table 2

Long-term carcinogenicity bioassay on APM administered ad libitum with feed to Sprague-Dawley rats from 8 weeks of age (BT6008): lymphoid and myeloid tumours.

GRO-UP	DOSE PPM (mg/kg bw)	ANIMALS		ANIMALS BEARING HLRN A
		ANIMALS		LYMPHO-BLASTIC LYM-PHOMA		LYMPHO-BLASTIC LEUKE-MIA		LYMPHO-CYTIC LYM-PHOMA		IMMUNO-BLASTIC LYM-PHOMA			TOTAL LYMPH-OID TUMORS			MONO-CYTIC LEUKE-MIA			MYEL-OID LEUKE-MIA			HISTIO-CYTIC SAR-COMA			TOTAL MYEL-OID TUMORS
		SEX	NO.	NO.	%	NO.	%	NO.	%	NO.	%		NO.	%		NO.	%		NO.	%		NO.	%		NO.	%
I	100000	M	100	0	0.0	0	0.0	0	0.0	24	24.0	P = 0.016; *P = 0.026	24	24.0	P = 0.023; *P = 0.041	1	1.0		1	1.0		3	3.0		5	5.0
I	(5000)	F	100	1	1.0	0	0.0	2	2.0	11	11.0	P = 0.016; *P = 0.019	14	14.0	P = 0.028; *P = 0.043	2	2.0		2	2.0		7	7.0		11	11.0	P = 0.008; *P = 0.012
II	50000	M	100	0	0.0	0	0.0	0	0.0	13	13.0		13	13.0		1	1.0		0	0.0		6	6.0		7	7.0
II	(2500)	F	100	2	2.0	0	0.0	0	0.0	10	10.0	P = 0.030; *P = 0.053	12	12.0		4	4.0	P = 0.025; *P = 0.025	1	1.0		8	8.0	*P = 0.053	13	13.0	P = 0.002; *P = 0.003
III	10000	M	100	0	0.0	1	1.0	0	0.0	8	8.0		9	9.0		2	2.0		1	1.0		3	3.0		6	6.0
III	(500)	F	100	2	2.0	0	0.0	2	2.0	3	3.0		7	7.0		2	2.0		0	0.0		10	10.0	P = 0.015; *P = 0.022	12	12.0	P = 0.004; *P = 0.006
IV	2000	M	150	0	0.0	0	0.0	1	0.7	15	10.0		16	10.7		7	4.7		0	0.0		10	6.7		17	11.3
IV	(100)	F	150	5	3.3	1	0.7	1	0.7	8	5.3		15	10.0		4	2.7		1	0.7		8	5.3		13	8.7	P = 0.021; *P = 0.043
V	400	M	150	0	0.0	0	0.0	0	0.0	22	14.7		22	14.7		1	0.7		0	0.0		2	1.3		3	2.0
V	(20)	F	150	7	4.7	0	0.0	2	1.3	8	5.3		17	11.3		5	3.3	*P = 0.030	0	0.0		9	6.0		14	9.3	P = 0.013; *P = 0.026
VI	80	M	150	3	2.0	0	0.0	0	0.0	12	8.0		15	10.0		2	1.3		2	1.3		4	2.7		8	5.3
VI	(4)	F	150	3	2.0	0	0.0	5	3.3	6	4.0		14	9.3		2	1.3		0	0.0		6	4.0		8	5.3
VII	0	M	150	0	0.0	1	0.7	0	0.0	19	12.7	#P = 0.0006	20	13.3	#P = 0.0022	2	1.3		1	0.7		8	5.3		11	7.3
VII	(0)	F	150	2	1.3	0	0.0	2	1.3	5	3.3	#P = 0.0015	9	6.0		0	0.0		0	0.0	#P = 0.0060	4	2.7		4	2.7	#P = 0.0473

[i] ^a Percentages refer to the number of animals at start.

New statistical analyses (in bold):

* One-tailed Fisher’s exact test ; ** Two-tailed Fisher’s exact test.

# Cochran–Armitage test for trend.

Table 3

Long-term carcinogenicity bioassay on APM administered ad libitum with feed to Sprague-Dawley rats from prenatal life (BT6009): animals bearing HLRN, lymphoma (all types), histiocytic sarcoma, leukemia (all types).

GROUP	DOSE PPM (mg/kg bw)	ANIMALS		ANIMALS BEARING HLRN^a				LYMPHOMAS (ALL TYPES)^a				HISTIOCYTIC SARCOMA^a		LEUKEMIAS (ALL TYPES)^a
GROUP	DOSE PPM (mg/kg bw)	SEX	NO.	NO.	%			NO.	%			NO.	%		NO.	%
I	2000	M	70	10	14.3			9	12.9				0	0.0	1	1.4
I	(100)	F	70	21	30.0	••	P = 0.005; *P = 0.010	16	22.9	•	P = 0.027, *P = 0.050	1	1.4	4	5.7	•	P = 0.031; *P = 0.031
II	400	M	70	9	12.9			6	8.6			1	1.4	2	2.9
II	(20)	F	70	12	17.1			11	15.7			0	0.0	1	1.4
III	0	M	95	8	8.4			8	8.4			0	0.0	0	0.0
III	(0)	F	95	12	12.6	◊◊	#P = 0.0045	10	10.5	◊	#P = 0.0368	2	2.1	0	0.0	◊	#P = 0.0106

[i] ^a Percentages refer to the number of animals at start.

Previous statistical analyses (Tibaldi et al., 2020):

• Statistically significant (P ≤ 0.05) using Chi2 or Fisher exact test.

•• Statistically significant (P ≤ 0.01) using Chi2 or Fisher exact test.

◊ Near the control incidence are the p-values (P ≤ 0.05) associated with the Cochran Armitage for the analysis of the trend.

◊◊ Near the control incidence are the p-values (P ≤ 0.01) associated with the Cochran Armitage for the analysis of the trend.

New statistical analyses (in bold):

* One-tailed Fisher’s exact test; ** Two-tailed Fisher’s exact test.

# Cochran–Armitage test for trend.

Table 4

Long-term carcinogenicity bioassay on APM administered ad libitum with feed to Sprague-Dawley rats from prenatal life (BT6009): lymphoid and myeloid tumours.

GROUP	DOSE PPM (mg/kg bw)	ANIMALS		ANIMALS BEARING HLRN^a
		ANIMALS		LYMPHO-BLASTIC LYMPHOMA		LARGE GRANULAR LYMPHOCYTE LEUKEMIA		LYMPHO-CYTIC LYMPHOMA		IMMUNO-BLASTIC LYMPHOMA		PLASMA-CYTIC LYMPH-OMA		TOTAL LYMPH-OID TUMORS			MONO-CYTIC LEUK-EMIA		MYELOID LEUKEMIA				HISTIO-CYTIC SARCOMA		TOTAL MYELOID TUMORS
		SEX	NO.	NO.	%	NO.	%	NO.	%	NO.	%	NO.	%	NO.	%		NO.	%	NO.	%			NO.	%	NO.	%
I	2000	M	70	6	8.6	1	1.4	0	0.0	3	4.3	0	0.0	10	14.3		0	0.0	0	0.0			0	0.0	0	0.0
I	(100)	F	70	5	7.1	0	0.0	7	10.0	3	4.3	1	1.4	16	22.9	P = 0.027; *P = 0.050	2	2.9	2	2.9			1	1.4	5	7.1
II	400	M	70	5	7.1	0	0.0	0	0.0	1	1.4	0	0.0	6	8.6		2	2.9	0	0.0			1	1.4	3	4.3
II	(20)	F	70	5	7.1	0	0.0	3	4.3	3	4.3	0	0.0	11	15.7		1	1.4	0	0.0			0	0.0	1	1.4
III	0	M	95	4	4.2	0	0.0	0	0.0	4	4.2	0	0.0	8	8.4		0	0.0	0	0.0			0	0.0	0	0.0
III	(0)	F	95	3	3.2	0	0.0	5	5.3	2	2.1	0	0.0	10	10.5	#P = 0.0368	0	0.0	0	0.0	◊	#P = 0.0324	2	2.1	2	2.1	#P = 0.0485

[i] Previous statistical analyses (Tibaldi et al., 2020):

^a Percentages refer to the number of animals at start.

• Statistically significant (P ≤ 0.05) using Chi2 or Fisher exact test.

•• Statistically significant (P ≤ 0.01) using Chi2 or Fisher exact test.

◊ Near the control incidence are the p-values (P ≤ 0.05) associated with the Cochran Armitage for the analysis of the trend.

◊◊ Near the control incidence are the p-values (P ≤ 0.01) associated with the Cochran Armitage for the analysis of the trend.

New statistical analyses (in bold):

* One-tailed Fisher’s exact test ; ** Two-tailed Fisher’s exact test.

# Cochran–Armitage test for trend.

Table 5

Long-term carcinogenicity bioassay on APM administered ad libitum with feed to Swiss mice from prenatal life (BT6010): animals bearing HLRN, lymphoma (all types), histiocytic sarcoma, leukemia (all types).

GROUP	DOSE PPM (mg/kg bw)	ANIMALS		ANIMALS BEARING HLRN^a			LYMPHOMAS (ALL TYPES)^a		HISTIOCYTIC SARCOMA^a		LEUKEMIAS (ALL TYPES)^a
GROUP	DOSE PPM (mg/kg bw)	SEX	NO.	NO.	%		NO.	%	NO.	%	NO.	%
I	32000	M	83	12	14.5		3	3.6	0	0.0	9	10.8	P = 0.007; *P = 0.009
I	(4000)	F	62	25	40.3		12	19.4	2	3.2	11	17.7
II	16000	M	64	12	18.8	*P = 0.040	2	3.1	0	0.0	10	15.6	P = 0.001; *P = 0.001
II	(2000)	F	64	16	25.0		6	9.4	2	3.1	8	12.5
III	8000	M	62	10	16.1		1	1.6	0	0.0	9	14.5	P = 0.001; *P = 0.001
III	(1000)	F	73	24	32.9		9	12.3	1	1.4	14	19.2
IV	2000	M	103	10	9.7		1	1.0	0	0.0	9	8.7	P = 0.018; *P = 0.026
IV	(250)	F	122	54	44.3		16	13.1	4	3.3	34	27.9	P = 0.007; *P = 0.014
V	0	M	117	10	8.5		7	6.0	1	0.9	2	1.7	#P = 0.0492
V	(0)	F	102	39	38.2		18	17.6	7	6.9	14	13.7

[i] ^a Percentages refer to the number of animals at start.

HLRN data unpublished.

New statistical analyses (in bold):

* One-tailed Fisher’s exact test; ** Two-tailed Fisher’s exact test.

# Cochran–Armitage test for trend.

Table 6

Long-term carcinogenicity bioassay on APM administered ad libitum with feed to Swiss mice from prenatal life (BT6010): lymphoid and myeloid tumours.

GROUP	DOSE PPM (mg/kg bw)	ANIMALS		ANIMALS BEARING HLRN^a
		ANIMALS		LYMPHO-BLASTIC LYMPHOMA		LYMPHO-BLASTIC LEUKEMIA			LYMPHO-CYTIC LYMPHOMA		IMMUNO-BLASTIC LYMPHOMA		TOTAL LYMPHOID TUMORS		MONO-CYTIC LEUKEMIA			MYELOID LEUKEMIA		HISTIO-CYTIC SARCOMA		TOTAL MYELOID TUMORS
		SEX	NO.	NO.	%	NO.	%		NO.	%	NO.	%	NO.	%	NO.	%		NO.	%	NO.	%	NO.	%
I	32000	M	83	2	2.4	6	7.2	P = 0.021; *P = 0.021	1	1.2	0	0.0	9	10.8	0	0.0		3	3.6	0	0.0	3	3.6
I	(4000)	F	62	7	11.3	6	9.7	P = 0.021; *P = 0.021	3	4.8	2	3.2	18	29.0	4	6.5		1	1.6	2	3.2	7	11.3
II	16000	M	64	0	0.0	4	6.3	P = 0.054; *P = 0.054	0	0.0	2	3.1	6	9.4	3	4.7	P = 0.043; *P = 0.043	3	4.7	0	0.0	6	9.4	P = 0.024; *P = 0.024
II	(2000)	F	64	5	7.8	7	10.9	P = 0.054; *P = 0.054	0	0.0	1	1.6	13	20.3	1	1.6	P = 0.043; *P = 0.043	0	0.0	2	3.1	3	4.7	P = 0.024; *P = 0.024
III	8000	M	62	1	1.6	8	12.9	P = 0.001; *P = 0.001	0	0.0	0	0.0	9	14.5	1	1.6		0	0.0	0	0.0	1	1.6
III	(1000)	F	73	6	8.2	12	16.4	P = 0.001; *P = 0.001	1	1.4	2	2.7	21	28.8	2	2.7		0	0.0	1	1.4	3	4.1
IV	2000	M	103	1	1.0	4	3.9	P = 0.012; *P = 0.016	0	0.0	0	0.0	5	4.9	1	1.0		4	3.9	0	0.0	5	4.9
IV	(250)	F	122	8	6.6	25	20.5	P = 0.012; *P = 0.016	8	6.6	0	0.0	41	33.6	6	4.9		3	2.5	4	3.3	13	10.7
V	0	M	117	2	1.7	1	0.9		0	0.0	5	4.3	8	6.8	0	0.0		1	0.9	1	0.9	2	1.7
V	(0)	F	102	7	6.9	9	8.8		2	2.0	9	8.8	27	26.5	4	3.9		1	1.0	7	6.9	12	11.8

[i] ^a Percentages refer to the number of animals at start.

HLRN data unpublished.

New statistical analyses (in bold):

* One-tailed Fisher’s exact test ; ** Two-tailed Fisher’s exact test.

# Cochran–Armitage test for trend.

References

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DOI: https://doi.org/10.5334/aogh.4163 | Journal eISSN: 2214-9996

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Language: English

Submitted on: May 3, 2022

Accepted on: May 26, 2023

Published on: Jun 20, 2023

Published by: Ubiquity Press

In partnership with: Paradigm Publishing Services

Publication frequency: 1 issue per year

Keywords:

cancer,

© 2023 Federica Gnudi, Simona Panzacchi, Eva Tibaldi, Martina Iuliani, Daria Sgargi, Luciano Bua, Daniele Mandrioli, published by Ubiquity Press
This work is licensed under the Creative Commons Attribution 4.0 License.

Volume 89 (2023): Issue 1