TRANSGENIC CROPS: BIOSAFETY ISSUES AND REGULATORY FRAMWEWORK IN INDIA

Dr. T.V. Ramanaiah Biotech Regulatory Affairs Manager, PHI Seeds Ltd, Hyderabad. Training Workshop on Biosafety for State Agricultural Universities 29th December, 2006 at Bhubaneswar 1

Biosafety Protecting human & animal health and environment from the possible adverse effects of the products of modern biotechnology

Precautionary Approach is adopted for assessment of Biosafety

2

Objectives of Regulations To facilitate & regulate Modern biotechnology work at different stages to achieve the objectives of biosafety.

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BIOSAFETY REGULATIONS & GUIDELINES * International: Cartagena Protocol on Biosafety OECD Guidelines * Country specific: USA, EU, Canada, Australia, Egypt, Japan, China, Philippines, Thailand, India, Pakistan, etc. 4

GENETICALLY MODIFIED ORGANISMS (GMOs) AND r-DNA PRODUCTS GOVERNED BY

Environment (Protection) Act, 1986 Came into force from 23.05.1986

Rules, 1989 on GMOs Notified on 05.12.1989 Came into force from 01.10.1993

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TRANSGENIC CROPS ARE ALSO GOVERNED BY ¾Industries (Development & Regulation) Act, 1951 - New Industrial Policy & Procedures, 1991 ¾ Seeds Act, 1966 ¾ Seeds Rules, 1968 ¾ Seeds (Control) Order, 1983 ¾ Seeds Policy, 1988, 2002 ¾ Protection of Plant Varieties and Farmers’ Rights Act, 2001 6

The Indian Environment (Protection) Act (EPA), 1986 ¾ Came into force from 23.5.1986. ¾ Provides protection and improvement of Environment. ¾ “Environment” includes water, air and land and the interrelationship , which exists among and between water, air and land, and human beings, other living creatures, plants, microorganism and property ¾ “Environmental pollutant” means any solid, liquid or gaseous substance present in such concentration as may be, or tend to be, injurious to environment. ¾ “Environmental pollution” means the presence in the environment of any environmental pollutant. contd ...... 7

Some Important Sections of EPA Section -15 ¾ Whoever fails to comply with or contravenes the act or any

rules can be punished with imprisonment for a term up to 5 years, or with a fine up to Rs. 100,000 or with both. ¾ If failure or contravention continues beyond one year, the

offender may be punishable with imprisonment which may extend up to 7 years.

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Rules for the Manufacture, Use / Import / Export and Storage of Hazardous Microorganisms, Genetically Engineered Organisms or Cells (Rules 1989) * Notified in exercise of powers under sections 6,8 & 25 of the EPA, 1986 on 5thDec’89. * Rules are came into force from 01.10.1993.

Application of Rules : *

Manufacture, import and storage of microorganisms and Gene-technological products.

* Genetically engineered organisms, microorganisms and cells and correspondingly to any substances and products and food stuffs, etc. *

Sale, any kind of handling, exportation, importation, production, manufacture, processing, storage, drawing off, packaging, repackaging of GMOs and drugs & pharmaceuticals, food stuffs etc. from GMOs and Gene technology products. 9

Approval and prohibitions, etc. under Rules, 1989 • No person shall import, export, transport, manufacture, process, use or sell any GMOs, substances or cells except with the approval of the GEAC. • Use of pathogenic organisms or GMOs or cells for research purpose shall be allowed under the Notification, 1989 of the EPA, 1986. •

Any person operating or using GMOs for scale up or pilot operations shall have to obtain permission from GEAC.

• Deliberate or unintentional release of GMOs not allowed. • Production in which GMOs are generated or used shall not be commenced except with the approval of GEAC.

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Approval and prohibitions, etc. under Rules 1989 ™ GEAC supervises the implementation of rules and guidelines. ™ GEAC carries out supervision through SBCC, DLC or any authorized person. ™ If orders are not complied, SBCC/DLC may take suitable measures at the expenses of the person who is responsible. ™ In case of immediate interventions to prevent any damage, SBCC and DLC can take suitable measures and the expenses incurred will be recovered from the person responsible.

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Approval and prohibitions, etc. under Rules 1989 *

All approvals shall be for a period of 4 years at first instance renewable for 2 years at a time.

*

GEAC shall have powers to revoke approvals in case of: a) Any new information on harmful effects of GMOs. b) GMOs cause such damage to the environment as could not be envisaged when approval was given. c) Non compliance of any conditions stipulated by GEAC.

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COMPETENT AUTHORITIES 1.

Recombinant DNA Advisory Committee (RDAC)

2.

Review Committee on Genetic Manipulation (RCGM)

3.

Institutional Biosafety Committee (IBSC)

4.

Genetic Engineering Approval Committee (GEAC)

5.

State Biotechnology Co-ordination Committee (SBCC)

6.

District Level Committee (DLC) 13

Recombinant DNA Advisory Committee (RDAC)

Main functions • Review developments in Biotechnology at National and

International level. • Recommend suitable and appropriate safety regulations for India in r-DNA research, use and applications.

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Review Committee on Genetic Manipulation Main functions • To bring out manuals of guidelines specifying procedures for regulatory process on GMOs in research, use and applications including industry with a view to ensure environmental safety. • To review all on going r-DNA projects involving high risk category and controlled field experiments. • To lay down procedures for restriction or prohibition, production, sale, import & use of GMOs both for research and applications. • To permit experiments with category III risks and above with appropriate containment. • To authorize imports of GMOs/ transgenes for research purposes. • To authorize field experiments in 20 acres in multi-locations in one crop season with up to one acre at one site. • To generate relevant data on transgenic materials in appropriate systems.

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Institutional Bio-Safety Committee (IBSC) Main functions • • • • • • •

To note and to approve r-DNA work. To ensure adherence of r-DNA safety guidelines of government. To prepare emergency plan according to guidelines. To recommend to RCGM about category III risk or above experiments and to seek RCGM’s approval. To inform DLC and SBCC as well as GEAC about the experiments where ever needed. To act as nodal point for interaction with statutory bodies. To ensure experimentation at designated location, taking into account approved protocols.

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Genetic Engineering Approval Committee (GEAC) Main functions •

To permit the use of GMOs and products thereof for commercial applications.

•

To adopt procedures for restriction or prohibition, production, sale, import & use of GMOs both for research and applications under EPA.

•

To authorize large scale production and release of GMOs and products thereof into the environment.

•

To authorize agencies or persons to have powers to take punitive actions under the EPA.

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State Biotechnology Co-Ordination Committee (SBCC) Main functions • Powers to inspect, investigate and to take punitive action in case of violations of statutory provisions through the State Pollution Control Board or the Directorate of Health etc. • To review periodically the safety and control measures in various institutions handling GMOs. • To act as nodal agency at State level to assess the damage, if any, due to release of GMOs and to take on site control measures.

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District Level Committee (DLC) Main functions •

To monitor the safety regulations in installations.

•

Have powers to inspect, investigate and report to the SBCC or the GEAC about compliance or non compliance of r-DNA guidelines or violations under EPA.

•

To act as nodal agency at District level to assess the damage, if any, due to release of GMOs and to take on site control measures.

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Agencies Involved in Rules,1989 of EPA 1986 GOVERNMENT OF INDIA Min. of Environment

Applicant

Large Scale Imports, Production and Release

GEAC

SBCC

DLC

Dept. of Biotechnology

RCGM

IBSC

PI/ Applicant

MEC

Preparation of guidelines, protocols, R&D work, limited experimental field trials and imports for R&D.

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r-DNA GUIDELINES

1990

“ Recombinant DNA Safety Guidelines”

1994

“ Revised Guidelines for Safety in Biotechnology”

1998

“ Revised Guidelines for Research in Transgenic Plants & Guidelines for Toxicity and Allergenicity Evaluation of Transgenic Seeds, Plants and Plant Parts ”

1999

“Guidelines for Generating pre-clinical and Clinical data for r-DNA based Vaccines, Diagnostics and other Biologicals

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COVERAGE OF REVISED GUIDELINES- 1998 * *

* * * * * * *

Recombinant DNA Research on plants and statutory bodies dealing with r- DNA work. Classification of Genetic Engineering Experiments on plants a. Category - I b. Category - II c. Category - III Containment measures followed in above categories. Green House / Design for Field evaluation of transgenic plants. Monitoring - cum - Evaluation Committee. Biosafety aspects of the transgenic plants. Import and shipment of genetically modified plants for research use only. Toxicity guidelines for testing transgenic plants and plant parts. Application for seeking approval under EPA for transgenic crops. 22

CLASSIFICATION OF GENETIC ENGINEERING EXPERIMENTS CATEGORY - I

CATEGORY - II

CATEGORY - III

Work involving defined gene(s)/DNA of microbial, plant and animal origin which are Generally Considered as safe for humans, animals & plants.

Work involving defined gene(s)/DNA of microbial, plant and animal origin which are non- pathogenic to humans and animals but can have implications on plants and insects.

Work involving defined gene(s)/DNA of microbial, plant and animal origin which can cause alterations in the biosphere and does not fall in category I & II .

Routine recombinant DNA experiments in lab.

Lab & Green House/Net House experiments in contained environment (except contained limited field trials.)

All experiments including Lab, Green House, limited contained field trials and limited experimental field trials etc. of category I & II.

IBSC can approve the experiments.

IBSC can approve the experiments with intimation to RCGM.

Experiments to be carried out only after RCGM’s approval.

Monitoring - cum - Evaluation Committee (MEC) Main functions • • • • • •

To undertake field visits at the experimental site (s). To review the design of experiments / trials and collection of data during limited open field trials. To collect information on the comparative agronomic advantages of transgenic crop. To assess and advise on the risks and benefits from the use of transgenic plants. To assist in collecting, consolidating and analyzing field data for evaluating environmental risks emanating from transgenic plants. To recommend those transgenic crops which would be found to be environmentally safe and economically viable to RCGM and to GEAC for consideration to release into the environment. 24

CONSTITUTION OF TASK FORCES/ SUBGROUPS ON BIOSAFETY REGULATIONS Ministry of Agriculture constituted a Task Force on ‘Applications of Agricultural Biotechnology’

Ministry of Environment & Forests constituted a Task Force on ‘Recombinant Pharma Sector Ministry of Environment had constituted two sub groups on streamlining biosafety regulations on Bt. cotton and other transgenic crops. 25

Flow Diagram on the recommended Procedure for New hybrid/variety with new gene Institutional Biosafety Committee (IBSC) Review Committee on Genetic Manipulation (RCGM) (green house experiments, contained field trials i.e. in-house trials/initial hybrid trials, generation of data on gene stability and expression, confirmation of the gene/event, etc)

RCGM [approval for conduct of multi-location field trials on the selected varieties)/ hybrids ]

Monitoring-cum-Evaluation Committee (MEC) –through SAU [evaluation of multi-location field trials data and recommending to GEAC under intimation to RCGM on the suitable varieties) /hybrids for large-scale trials (LST)]

Genetic Engineering Approval Committee (GEAC) Large Scale Trials (LST)

Seed Production 10 ha

Large Scale Trials (LST)

Seed Production100 ha

ICAR trials 1st Year ICAR trials 2nd Year

MEC

GEAC (environmental clearance of the event/gene in a given background)

Material cleared from Environmental sensitivity by MoEF/or otherwise 26

Amendments/ New Initiatives in the Guidelines ¾

Defining small experimental field trials

¾

Large scale fermentation experiments

¾

Pre-release Monitoring of field trials through the SAUs

¾

Post-release assessment of transgenic crops through the SAUs

¾

Empowering Seed Inspectors to draw samples of transgenic seeds under EPA & Seeds Act

¾

Streamlining the procedure for import of refined & de-gummed soy oil

¾

Notification through the DGFT on import of GMOs and products thereof for different purposes 27

Biosafety parameters on Transgenic crops A.

General information ¾

Rationale for the development: in terms of agronomic, nutritional and other benefits ¾ Characteristics of the host plant: in terms of seed setting; germination rates; novel phenotypic features; back crossing duration; implications of toxicity and allergenicity, if any during handling, etc ¾ Mode of Pollination: ¾ Centres of Origin/diversity of the crop species ¾ Geographical distribution of the target crop and sexually compatible plant species including wild relatives contd ....... 28

B. Biosafety Parameters: 1. Genetic and Molecular parameters ¾ Genetic analysis including copy number of inserts: source and sequence of gene (s); characteristics of expression vector (s); characteristics of inserted gene (s) with detailed sequences; characteristics of promoters (tissue specific/constituent); marker gene (s) (expression of marker gene (s) in plant/ tissue specific and their environmental implications) ¾ Stability of the gene: in different plant parts; successive generations; pattern of inheritance ¾ Level, site(s) and duration of expression of transgene (s): estimation of individual products & final product in different plant parts, i.e. roots, leaves, stem, seeds. ¾

Characterization of expressed gene product

¾ Efficacy/utility of gene product ¾ Compositional analysis

contd .... 29

Biosafety parameters on Transgenic crops Information to be generated at field level

2. Environmental parameters ¾ Gene flow: To understand the behavior of the pollen and their viability and ability to transfer the gene (s). ¾ Implications of out-crossing: Stability and expression of the gene (s) in other rice lines/hybrids; transfer of non-desired characters,

¾ Effect on pests and beneficial organisms: Changes in the dynamics of pest infestation, presence of insects and also beneficial insects,

¾ Effect on soil biota: Symbiotic micro-flora, if any, water ecosystem, etc.

Contd…. 30

3.

Biosafety parameters on Transgenic crops Agronomic parameters

¾ Presence of the gene at phenotypic level: Influence of agricultural conditions on the expression of gene (s) product (s); levels of product expression in different plant parts at different growth cycle; weed formation; invasiveness.

¾ Growth and developmental parameters: Normal/ different or changes are insignificant

¾ Yield: Comparative or advantage; special conditions/quantification methods

¾ Responses to diseases: Susceptible or resistant to major diseases

¾ Quality parameters:

¾ Economic evaluation/ cost: benefit ratio: Value addition to farmers; risks and benefit to the society, etc Contd…. 31

Biosafety parameters on Transgenic crops 4.

Toxicity parameters including histo-pathological studies (need based)

¾ Food/feed safety evaluation in animals such as: * Effect on small laboratory animals * Effect on livestock animals (representative goat studies of large animals) * Effect on birds/ avian species * Effect on fish Contd…. 32

Biosafety parameters on Transgenic crops 5.

Allergenicity parameters (need based) ¾ Primary skin irritation test in rabbit/ guinea pigs ¾ Irritation to mucous membrane test in rabbit/ guinea pig ¾ Immunological responses in suitable animal system Contd….

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GUIDELINES FOR TOXICICTY AND ALLERGENICITY EVALUATION OF TRANSGENIC SEEDS, PLANTS AND PLANT PARTS Guidelines for Toxicity evaluation of transgenic seeds ™ ™ ™ ™ ™ ™ ™ ™ ™

Acute oral toxicity test of transgenic seeds in Rat Sub-chronic (90 days) oral toxicity test of transgenic seeds in Rat Sub-chronic oral toxicity – Goats – 90 days study Feeding studies of transgenic plants/plant parts in Lactating Crossbred Dairy Cows Feeding studies of transgenic plants/plant parts in Chicken. Feeding studies of transgenic plants/plant parts in Catfish Primary skin irritation test of transgenic seeds in Rabbit Irritation to mucous membrane test of transgenic sees in female Rabbit Skin sensitization test of transgenic seeds in Guinea pigs 34

GUIDELINES FOR TOXICICTY AND ALLERGENICITY EVALUATION OF TRANSGENIC SEEDS, PLANTS AND PLANT PARTS Guidelines for Toxicity evaluation of transgenic vegetables ™ Acute oral toxicity test of transgenic vegetables in Rat ™ Sub-chronic (90 days) oral toxicity test of transgenic vegetables in Rat ™ Primary skin irritation test of transgenic vegetables in Rabbit ™ Irritation to mucous membrane test of transgenic vegetables in female Rabbit

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GUIDELINES FOR TOXICICTY AND ALLERGENICITY EVALUATION OF TRANSGENIC SEEDS, PLANTS AND PLANT PARTS Guidelines for Toxicity evaluation of transgenic leaves ™

Sub-chronic (90 days) oral toxicity test of transgenic leaves in male Rabbit

Protocol for Allergenicity testing of genetically transformed products in Animal Model ™

Passive Cutaneous Anaphylaxis (PCA) test

™

Pransnitz-Kustner (PK) test

™

Radioallergosorbent (RAST)/RAST inhibition test

™

Enzyme Linked Immunosorbent Assay (ELISA) 36

TRANSGENIC CROPS APPROVED GOBALLY Sl. No. CROP 1.

Canola

TRAIT

COUNTRY

YEAR

Herbicide Tolerance (CP4EPSPS)

Canada US Japan

1995 1999 1996

Herbicide Tolerance (PAT)

Canada US Japan Australia

1995 1995 1996 2003

Herbicide Tolerance (bxn)

Canada Japan

1997 1998

Herbicide Tolerance (ALS)

Canada

1995 contd…

37

Sl. No. CROP

TRAIT

COUNTRY

YEAR

2. Carnation

Increased shelf life Herbicide Tolerance

Australia European Union

1995 1998

3. Chicory

Herbicide Tolerance

European Union USA

1996 1997

4. Cotton

Insect Tolerance

USA Australia Japan China Mexico South Africa Argentina India

1995 1996 1997 1997 1997 1997 1998 2002

USA Japan

1994 1997

Herbicide Tolerance (bxn gene)

contd…

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Sl. No. CROP

TRAIT

COUNTRY

YEAR

Cotton Herbicide Tolerance (bxn gene) Insect Tolerance

USA Japan

1997 1998

Cotton Herbicide Tolerance (ALS gene)

USA

1996

Cotton Herbicide Tolerance (CP4EPSPSgene) USA Japan Australia Argentina

1995 1997 1999 2000

Cotton Herbicide Tolerance (CP4EPSPSgene) USA Insect Tolerance Cotton Herbicide Tolerance (PATgene) Cotton

USA

2003

Insect Tolerance (Cry1Ac+Cry1F genes) USA

2004 Contd…

39

Sl. No. CROP

COUNTRY

YEAR

Canada USA

1996 1999

Insect Tolerance USA Herbicide Tolerance(CP4EPSPS gene) Canada Japan

1996 1996 1997

5.

Linseed

6.

Maize

TRAIT Herbicide Tolerance (ALS gene)

Maize Herbicide Tolerance (PAT gene)

USA Canada Japan Argentina

1995 1996 1997 1998

Maize Herbicide Tolerance (PAT gene) Insect Tolerance

USA Canada Japan Argentina EU

1995 1996 1996 1996 1997

Contd…

40

Sl. No. CROP

TRAIT

COUNTRY

YEAR

Maize Herbicide Tolerance (PAT gene)

USA Canada

1996 1996

Maize Herbicide Tolerance (DAM gene)

USA

1998

Maize Insect Tolerance ( cry3Bb1 gene)

USA Canada

2003 2003

7. Melon

Delayed Ripening

8. Polish Canola Herbicide Tolerance (PAT gene)

USA Canada

1998

Polish Canola Herbicide Tolerance (CP4EPSPS gene) Canada

1997

9. Potato Potato

Insect Tolerance (cry3A gene) Insect Tolerance (cry3A gene) Herbicide Tolerance (CP gene)

USA Canada USA Canada

1995 1995 1999 1999

Contd…

41

Sl. No. CROP 10.

COUNTRY

YEAR

USA

1999

Herbicide Tolerance (CP4EPSPS gene)

USA Argentina Japan Canada Uruguay Mexico Brazil South Africa

1994 1996 1996 1995 1997 1998 1998 2001

Soybean

Herbicide Tolerance (

Soybean

Modified Oil (fad gene)

USA Canada Japan USA Canada Japan

1996 1999 1999 1997 2000 1999

Rice

11. Soybean

TRAIT Herbicide Tolerance (PAT gene)

PATgene)

Contd…

42

Sl. No. CROP 12. 13.

14.

Squash

TRAIT

COUNTRY

Resistance to viral infection (cp gene) USA

YEAR 1994

Sugarbeet Herbicide Tolerance (CP4EPSPS gene)

USA

1998

Sugarbeet Herbicide Tolerance (PAT gene)

USA Canada

1998 2001

Tomato

Increased Shelf life (ACC gene)

USA

1995

Tomato

Insect Tolerance

USA

1998

Tomato

Delayed ripening

(SAMase gene)

USA

1996

Tomato

Delayed ripening

(ACCD gene)

USA

1995

Tomato

Delayed ripening (PG gene)

USA 1992 Mexico 1995, Japan 1996 43

TRANSGENIC CROPS APPROVED IN ININDIA ¾

Only one crop approved i.e. Bt. cotton

¾ Genes/events approved are cry1Ac/Mon 531event ,

cry1Ac & cry2Ab/ Mon 15985 event, cry1Ac/Event No.1, and GFM cry1A gene ¾

Three hybrids approved in 2002, one in 2004, 16 hybrids in 2005 and 62 hybrids in 2006.

¾

More hybrids under large scale trials 44

Field trials on transgenic food crops conducted during 2006 Sl.No. Name of the Company/institution

Crops

Gene/genes

Traits of the gene

1. IARI, Pusa , New Delhi

Brinjal

cry1Aa and cry1Aabc

Shoot & fruit borer (Leucinodes orbonalis) resistance resistance

2. M/s Maharashtra Hybrid Seeds Company Limited, Mumbai

Brinjal

cry1Ac

fruit and shoot borer (Leucinodes orbonalis), gram caterpillar/ fruit borer (Helicoverpa armigera) and stem borer (Euzophera perticella) resistance

3. M/s. Sungro Seeds Research Ltd., Delhi

Brinjal

cry1Ac

Shoot & fruit borer (Leucinodes orbonalis) resistance

4.

M/s. Nunhems India Pvt. Ltd., Gurgaon

Cabbage

cry1Ba and cry1Ca

Diamond Back Moth (DBM) (Plutella xylostella) resistance

5.

Directorate of Oilseeds Research (DOR), Rajendranagar, Hyderabad

Castor

cry1Aa and cry1Ec

resistance to the lepidopteron insect pests

6.

M/s. Sungro Seeds Research Ltd., Delhi

Cauliflower

cry1Ac

Diamond Back Moth (DBM) (Plutella xylostella) resistance 45

7.

M/s. Nunhems India Pvt. Ltd., Gurgaon

Cauliflower

cry1Ba and cry1Ca

Diamond Back Moth (DBM) (Plutella xylostella) resistance

8.

M/s Monsanto India Ltd, Mumbai

Corn

cry1Ab gene (Mon 810 event)

Chilo partellus, Sesamia inferens and Helicoverpa armigera resistance

9.

ICRISAT, Hyderabad

Groundnut

chitinase gene from rice (Rchit)

resistance against the aflatoxin producing Aspergillus flavus

10. M/s Maharashtra Hybrid Seeds Company Limited, Mumbai

Okra

cry1Ac cry2Ab

fruit and shoot borer (Earis vittella) and fruit borer (Helicoverpa armigera) resistance

11. Central Potato Research Institute (CPRI), Shimla

Potato

RB gene late blight resistance derived from Solanum bulbocastanum

12. M/s Maharashtra Hybrid Seeds Company Limited, Mumbai

Rice

cry1Ac cry2Ab

Yellow Stem Borer (Scirpophaga incertulas) resistance

13. Tamil Nadu Agricultural University (TNAU)

Rice

rice chitinase (chi11) or tobacco osmotin gene

rice sheath blight fungus (Rhizoctonia Solani) resistance 46

14.

IARI, Pusa New Delhi

Rice

cry1B-cry1Aa fusion gene

15.

IARI, Pusa New Delhi

Tomato antisense replicase gene of tomato leaf curl virus

16.

M/s Maharashtra Hybrid Tomato cry2Ab Seeds Company Limited, Mumbai

Yellow Stem Borer (Scirpophaga incertulas) resistance

tomato leaf curl virus resistance

gram caterpillar/ fruit borer (Helicoverpa armigera) resistance

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CROPS UNDER FIELDTRIALS ¾

12 transgenic crops under various stages of contained field trials

¾

Include brinjal, cotton, cabbage, groundnut, pigeon pea, maize, mustard, potato, sorghum, tomato, tobacco, rice, okra and cauliflower

¾

Traits include insect resistance, herbicide tolerance, virus resistance, nutritional enhancement, salt tolerance, fungal resistance, etc 48

CONCLUSIONS ™ All r-DNA activities/ GMOs and products thereof are

regulated under the Rules- 1989 OF EPA- 1986. ™ The Rules, Procedures and Guidelines are sufficiently defined for Risk Assessment of transgenic crops, keeping in view the requirements of the country. ™ Sufficient infrastructure is available in public & private sectors to undertake risk assessment and food safety evaluation of transgenic crops / foods and other biochemical tests. ™ EPA to provide safe products to the society on the existing scientific knowledge. 49

THANK YOU

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